JP7014787B2 - Manufacturing method of the dosage product - Google Patents

Description

The present invention relates to a method for producing an administration preparation; granules (fine granules) and tablets obtained by the above method; use of surface-reactive calcium carbonate in such a method; an administration preparation containing the granules; pharmaceuticals, dietary supplements, pesticides, Use of the granules, or tablets and / or capsules, or the dosage product in cosmetics, household products, foods, packages and personal care products; and the granules, or tablets and / or capsules, or the dosage product. Including pharmaceuticals, dietary supplements, pesticides, cosmetics, household products, foods, packaging and personal care products;

The surface-reactive calcium carbonate powder can be used as a carrier in a very wide range of applications due to its high porosity and high carrier capacity (loading capacity) of the active / inactive agent. Therefore, surface-reactive calcium carbonate is thus becoming increasingly important in the manufacture of dosage products. Depending on the end use, the carrier material or matrix for such an dosage product must first be mixed with the required active ingredient or inert precursor material, and the dosage product can be manufactured. It is necessary to find a mixable formulation aid so that it can be mixed. Such a pharmaceutical product is mainly produced from a powdered product. However, such powders often cause problems such as not flowing freely, having a low bulk density, producing too much dust, and typically adhering to the device during further processing. Therefore, a method has been developed for producing a pharmaceutical product in the form of a compressed material containing surface-reactive calcium carbonate and avoiding the above-mentioned inconvenience.

For example, a pre-publication application, European Patent Application No. 15160194.5, refers to a method of making a dispersible dosage formulation, which comprises the following steps: a) Natural in an aqueous medium. To provide a functional calcium carbonate-containing material which is a reaction product of ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is treated with the acid. Formed in the field and / or supplied from an external source; b) providing at least one disintegrant; c) optionally providing at least one additional compounding aid; d) step a. Mixing the functional calcium carbonate-containing material of), at least one disintegrant of step b), and optionally at least one additional compounding aid of step c); e) the mixture obtained in step d). Compress with a roller compressor at a compaction pressure in the range of 2-20 bar to form a ribbon; f) crush the ribbon in step e) into granules; and g) granulate at least in step f). Sift one mesh size.

Pre-publication application, European Patent Application No. 14199037.4, refers to a method of making a drug delivery system, which comprises the following steps: a) Naturally ground calcium carbonate or natural ground calcium carbonate in an aqueous medium. To provide surface-reacted calcium carbonate, which is a reaction product of precipitated calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is formed in situ by treatment with the acid. / Or supplied from an external source; b) providing at least one pharmaceutically active agent or pharmaceutically inactive precursor thereof; c) providing at least one compounding aid; d) step a). Surface reaction of calcium carbonate, at least one pharmaceutically active agent of step b) or its pharmaceutically inactive precursor, and at least one compounding aid of step c); e) obtained in step d). The mixture is compressed by a roller compressor with a compaction pressure in the range of 4 to 20 bar; and f) the roller-compressed mixture obtained in step e) is compressed to obtain a drug delivery system.

Pre-publication application, European Patent Application No. 15197395.5, refers to a method of producing granules containing surface-reactive calcium carbonate, which method comprises the following steps: a) in an aqueous medium. To provide surface-reacted calcium carbonate, which is the reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors, wherein the carbon dioxide is used. Formed in situ by treatment with the _H3O ⁺ ion donor and / or supplied from an external source; b) providing one or more active ingredients in the form of a liquid; c) liquid. Saturating surface-reactive calcium carbonate to one or more active ingredients in the form of; d) providing one or more binders; and e) obtained in step c) under stirring in a stirrer. Saturated surface reaction Calcium carbonate is mixed with one or more binders in step d).

However, the methods described in the above literature need to be able to be mixed not only with the surface-reactive calcium carbonate powder but also with the activator used, and are more suitable for the desired end use. Use compounding aids such as binders and / or disintegrants that must be present (eg, those that must be approved for ingestion by humans and / or animals) during compression. However, it is sometimes required.

Thus, an dosage product that provides the same or better performance as an existing dosage product and makes it possible to produce a dosage product that is compressed specifically without a compounding aid such as a binder and / or a disintegrant. And there is a continuing need for methods for its manufacture. In addition, it has improved fluidity and improved loose bulk density and tap bulk density compared to when powdered, with significantly less dust or little dust, and therefore for further processing. A method capable of producing an administration formulation that may be easy to use is desirable.

Therefore, an object of the present invention is to provide a method for producing an administered preparation. Another object is to provide a highly efficient compression method for producing a dosage product. A further object is to provide a method of producing a dosage product that is compressed without a compounding aid such as a binder and / or a disintegrant. Another purpose is to have improved fluidity and improved loose bulk density and tap bulk density compared to when powdered, with significantly less dust or little dust, therefore. , To provide a method of producing a dosage product that may be easy to use for further processing.

One or more of the problems mentioned above and the other problems are solved by the subject matter described herein as independent claims. Advantageous embodiments of the invention are defined in the corresponding dependent claims.

The first aspect of the present invention relates to a method for producing an administered preparation. This method involves the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The carried surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form; and (e). ) The compressed form of step (d) is crushed into granules;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

According to another aspect of the invention, granules obtained by the methods defined herein are provided. According to a further aspect of the invention, tablets and / or capsules obtained by the methods defined herein are provided.

According to a further aspect of the present invention, a dosage product containing the granules defined herein, preferably a tablet, a mini-tablet or a capsule is provided.

According to yet another aspect of the invention, the granules defined herein, or defined herein, in pharmaceuticals, dietary supplements, pesticides, cosmetics, household products, foods, packages and personal care products. The use of tablets and / or capsules, or the pharmaceutical product as defined herein, is provided.

According to a further aspect of the invention, pharmaceuticals, dietary supplements, pesticides, comprising granules as defined herein, or tablets and / or capsules as defined herein, or pharmaceuticals as defined herein. Cosmetics, household products, foods, packaging and personal care products are provided.

According to another aspect of the invention, the use of surface reactive calcium carbonate in the methods defined herein is provided.

According to one embodiment of the method of the invention, the natural ground calcium carbonate is selected from calcium carbonate containing minerals selected from the group comprising marbles, caustic, dolomites, limestone, and mixtures thereof. Or the precipitated calcium carbonate is selected from the group comprising aragonite, precipitated calcium carbonate having a mineral crystalline form of batelite or calcite, and mixtures thereof.

According to another embodiment of the method of the present invention, the surface reaction calcium carbonate is
(A) Measured by the BET method using ISO9277 using nitrogen, 20 m ² / g to 450 m ² / g, preferably 20 m ² / g to 250 m ² / g, more preferably 30 m ² / g to 160 m ² . It has a BET specific surface area of / g, most preferably 40 m ² / g to 150 m ² / g, more preferably 40 m ² / g to 140 m ² / g; and / or (b) 1 μm to 50 μm, preferably. Includes particles with a volume median particle size _d50 of 1 μm to 45 μm, more preferably 2 μm to 30 μm, even more preferably 3 μm to 15 μm, most preferably 4 μm to 12 μm; and / or (c) mercury intrusion formula. Calculated from the measurement results with a porosimeter, 0.15 cm ³ / g to 1.35 cm ³ / g, preferably 0.30 cm ³ / g to 1.30 cm ³ / g, most preferably 0.40 cm ³ /. It has an in-particle penetration specific surface area in the range of g to 1.25 cm ³ / g.

According to yet another embodiment of the method of the invention, the at least one active ingredient and / or its inert precursor is a fragrance, flavor, herb extract, fruit extract, nutrient, trace mineral, repellent. Agents, foods, cosmetics, flame retardants, enzymes, polymers (macromolecules), pesticides, fertilizers, preservatives, antioxidants, reactive chemicals, synthetic, semi-synthetic or naturally occurring pharmaceutical activity It is selected from the group containing agents or pharmaceuticalally inactive precursors, and mixtures thereof.

According to one embodiment of the method of the invention, the at least one active ingredient and / or its inert precursor is in the form of a liquid, preferably the at least one active ingredient and / or its inactivity. An active precursor is provided in the solvent, preferably the solvent is water, methanol, ethanol, n-butanol, isopropanol, n-propanol, n-octanol, acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, vegetable oils and the like. It is selected from the group containing derivatives, animal oils and derivatives thereof, molten fats and waxes, and mixtures thereof, and more preferably, the solvent is water, ethanol and / or acetone.

According to another embodiment of the method of the present invention, the carrying step (c) involves spraying or dropping the at least one active ingredient and / or an inert precursor thereof onto the surface-reactive calcium carbonate, and flowing. This is done by mixing in a device selected from the group including floor dryers / granulators, plow shear mixers, vertical or horizontal mixers, high or low shear mixers, and high speed blenders.

According to yet another embodiment of the method of the present invention, the compression step (d) by the roller compressor is in the range of 1 to 28 kN / cm, more preferably in the range of 1 to 20 kN / cm, most preferably 2. It is performed with a roller compaction pressure in the range of ~ 10 kN / cm.

According to one embodiment of the method of the invention, the method further comprises the step (f) of sifting the granules of step (e) into at least one mesh size sieve.

According to another embodiment of the method of the invention, the method provides at least one compounding aid; and the granules obtained in step (e) and / or step (if performed). Mixing and / or coating step of mixing the granules obtained in f) with the at least one compounding aid of step (b1) and / or coating with the at least one compounding aid of step (b1). (C1) is further included.

According to yet another embodiment of the method of the invention, the at least one compounding aid is a disintegrant, preferably a modified cellulose gum, an insoluble crosslinked polyvinylpyrrolidone, a starch glycolate, a microcrystalline cellulose, a pregelatinized starch, and the like. Sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymer of N-vinyl-2-pyrrolidone, alkyl cellulose ester, hydroxyalkyl cellulose ester, carboxyalkyl cellulose ester, alginate, microcrystalline cellulose and its crystalline polymorph, ion exchange resin , Gum, chitin, chitosan, clay, gellan gum, crosslinked polacrilin copolymer, agar, gelatin, dextrin, acrylic acid polymer, sodium carboxymethyl cellulose / calcium, hydroxypropylmethyl cellulose phthalate, shelac, or mixtures thereof. Disintegrants; lubricants, especially internal and / or external lubricants; impact modifiers; plasticizers; waxes; stabilizers; pigments; colorants; flavoring agents; flavoring agents; flavoring agents; sweeteners; food It is selected from the group containing a sensation improver; a diluent; a film-forming agent; an adhesive; a buffer; an adsorbent; an odor masking agent; and a mixture thereof.

According to one embodiment of the method of the invention, the sieving step (f) is for sieving with different mesh sizes, preferably 180 μm, 250 μm, 355 μm, 500 μm and 710 μm. This is done by sieving the mesh size of.

According to another embodiment of the method of the invention, the method comprises granules obtained in step (e) or, if done, granules obtained in step (f) and / or step (c1) into a tablet. It further comprises a step (g) of filling the capsule with the granules obtained in step (e) or, if done, step (f) and / or the granules obtained in step (c1).

FIG. 1 shows a scanning electron microscope (SEM) photograph of granules made from surface-reactive calcium carbonate (FCC) carrying 10 wt% eugenol. FIG. 2 shows a scanning electron microscope (SEM) photograph of granules made from surface-reactive calcium carbonate (FCC) carrying 25% by weight eugenol. FIG. 3 shows a scanning electron microscope (SEM) photograph of granules made from surface-reactive calcium carbonate (FCC) carrying 10 wt% ibuprofen. FIG. 4 shows a scanning electron microscope (SEM) photograph of granules made from surface-reactive calcium carbonate (FCC) carrying 40% by weight ibuprofen.

For the purposes of the present invention, the terms described below are understood to have the meanings described below.

For the purposes of the present invention, an "acid" is defined as a Bronsted-Lowry acid, i.e., an _H3O ⁺ ion feeder. An "acid salt" is defined as an _H3O ⁺ ion feeder, eg, a hydrogen-containing salt, partially neutralized by an electrically positive element. A "salt" is defined as an electrically neutral ionic compound formed from anions and cations. A "partially crystalline salt" is defined as a salt that exhibits a substantially discrete diffraction image in X-ray diffraction (XRD) analysis.

According to the present invention, pK _a is a symbol representing an acid dissociation constant associated with a given ionizable hydrogen in a given acid, from this acid in equilibrium in water at a given temperature. It shows the original degree of dissociation of this hydrogen. Such pK _a values are derived from D.I. C. Harris, Quantitative Chemistry Analysis: 3rd Edition, 1991, W. et al. H. It can be found in reference textbooks such as Freeman (USA), ISBN 0-7167-2170-8.

A "surface-reactive calcium carbonate" is a material comprising calcium carbonate, preferably a water-insoluble, at least partially crystalline non-calcium carbonate salt extending from the surface of at least a portion of the calcium carbonate. The calcium ions that form at least the partially crystalline non-calcium carbonate salt are largely derived from the calcium carbonate material, which is a starting material that also serves to form the core of surface-reactive calcium carbonate. Such salts may contain OH ^- anions and / or water of crystallization.

In the significance of the present invention, the "water-insoluble" material is when a liquid filtrate is recovered by being mixed with deionized water and filtered at 20 ° C. using a filter having a pore diameter of 0.2 μm. The solid material recovered after evaporating 100 g of the above-mentioned liquid filtrate at 95 to 100 ° C. is defined as a material of less than 0.1 g or 0.1 g (0.1 g or less). A "water-soluble" material is defined as a material that results in a recovery of more than 0.1 g of solid material recovered after evaporation of 100 g of the liquid filtrate at 95-100 ° C.

In the sense of the present invention, the "specific surface area (SSA)" of calcium carbonate is defined as the surface area of the calcium carbonate divided by the mass of the calcium carbonate. The specific surface area used here is measured by nitrogen gas adsorption using BET isotherms (ISO 9277: 2010) and is defined in units of m ² / g.

The term "at least one active ingredient and / or its inactive precursor" is understood to be different from a compounding agent, i.e., this at least one active ingredient and / or its inactive precursor is bound. Agents (binders), disintegrants, lubricants, impact modifiers, plasticizers, waxes, stabilizers, pigments, colorants, flavoring agents, flavoring agents, flavoring agents, texture improving agents, diluents, film forming agents , Adhesives, buffers, adsorbents, odor masking agents, and mixtures thereof, and may not be these substances themselves.

In the sense of the present invention, the term "compression" means a decrease in volume and / or density and an increase in the hardness of the granules obtained under pressure.

When the term "comprising" is used herein and in the claims, it does not preclude other elements. For the purposes of the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising" described above. Hereinafter, if a group is defined to include at least a certain number of embodiments, it is also understood to preferably disclose a group consisting only of these embodiments.

If an indefinite or definite article, such as "a," "an," or "the," is used when referring to a singular noun, this is the noun's unless something else is explicitly stated. Includes plurals.

Terms such as "obtainable" or "definable" and "obtained (obtained)" or "defined (defined)" are used interchangeably. This means, for example, that the term "obtained (obtained)" may be referred to, for example, as an embodiment of the term "obtained (obtained)", unless the context clearly indicates that it is different. Although not meant to indicate that it must be obtained by the sequence of subsequent steps, such a limited understanding is, as a preferred embodiment, "obtained" or "defined". It means that it is always included in the term "to (defined)".

According to the present invention, the administered preparation is a surface-reactive calcium carbonate carrying at least one active ingredient and / or its inert precursor in the absence of a compounding aid such as a binder and / or a disintegrant. Can be manufactured by compressing. In addition, the manufactured dosage product has improved fluidity and improved loose bulk density and tap bulk density as compared to when made as a powder, with significantly less dust or almost no dust. It does not occur and can therefore be easy to use for further processing. In addition, the method of the present invention also provides the possibility of efficiently compressing the administered formulation.

Hereinafter, the above-mentioned steps regarding the method for producing the present invention, in particular the pharmaceutical product, will be described in more detail.

Method Step (a)
In step (a) in the method of the present invention, surface-reactive calcium carbonate is provided.

The surface reaction calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H ₃ O ⁺ ion donors, wherein the carbon dioxide is the H ₃ O ⁺ ion donor. Formed in-situ by processing in and / or supplied from an external source.

The _H3O ⁺ ion donor in the context of the present invention is a Bronsted acid and / or an acid salt.

An "acid salt" is defined as an _H3O ⁺ ion feeder, eg, a hydrogen-containing salt, partially neutralized by an electrically positive element. A "salt" is defined as an electrically neutral ionic compound formed from anions and cations. A "partially crystalline salt" is defined as a salt that exhibits a substantially discrete diffraction image in X-ray diffraction (XRD) analysis.

In a preferred embodiment of the invention, the surface-reactive calcium carbonate is obtained by a process comprising the following steps:
(A) Preparing a suspension of natural calcium carbonate or precipitated calcium carbonate,
(B) Add at least one acid having a pK _a value of 0 or less than 0 (0 or less) at 20 ° C. or a pK _a value of 0 to 2.5 at 20 ° C. to the suspension of step (a). And (c) treating the suspension of step (a) with carbon dioxide before step (b), during step (b) or after step (b).
According to another embodiment, the surface-reactive calcium carbonate is obtained by a process comprising the following steps:
(A) Preparing a suspension of natural calcium carbonate or precipitated calcium carbonate,
(B) Preparing at least one water-soluble acid,
(C) Preparing CO ₂ gas,
(D) Bringing the natural or precipitated calcium carbonate of step (A) into contact with at least one acid of step (B) and CO ₂ of step (C).
Here, the above process is characterized by the following (i) and (ii):
(I) At least one acid in step (B) has a pK _a greater than 2.5 and less than 7 or 7 (7 or less) at 20 ° C. in relation to its initially available ionization of hydrogen. Having and corresponding anions are formed when this initially available hydrogen, which can form water-soluble calcium salts, is lost; and (ii) at least one acid and natural calcium carbonate or precipitated calcium carbonate. Following contact with calcium, the hydrogen-containing salt has _a pKa of greater than 7 at 20 ° C. in relation to the ionization of the initially available hydrogen, the anion of which salt is a water-soluble calcium salt. If it can be formed, at least one water-soluble salt is further supplied.

"Natural Calcium Carbonate (GCC)" (also referred to as "Natural Calcium Carbonate") is preferably a carbonate containing a mineral (inorganic) selected from the group comprising marbles, whites, dolomites, limestones, and mixtures thereof. Selected from calcium. Naturally ground calcium carbonate can further contain naturally occurring components such as magnesium carbonate, aluminosilicate and the like.

In general, milling of naturally milled calcium carbonate can be a dry or wet milling step, for example under any conventional conditions where most milling occurs as a result of impact by a secondary object. It can be carried out using one or more of the following crushers: ball mills, rod mills, vibration mills, roll crushers, centrifugal impact mills, vertical bead mills, friction crushers, pin mills, hammer mills, etc. A crusher, shredder, de-clamper, knife cutter, or other such device known to those of skill in the art. When the calcium carbonate-containing mineral material contains a moist ground calcium carbonate-containing mineral material, the grinding step is under conditions such that spontaneous grinding occurs and / or by horizontal ball grinding and / or others known to those of skill in the art. It can be done by such a process. The wet-treated natural ground calcium carbonate-containing mineral material thus obtained is washed and dehydrated by a well-known method, for example, by forced evaporation before aggregation, filtration or drying. Subsequent drying steps (if necessary) can be done in a single step, such as spray drying, or in at least two steps. It is also common for such mineral materials to undergo a mineral processing step (eg, flotation, bleaching or magnetic separation) to remove impurities.

As used in the present invention, "precipitated calcium carbonate (PCC)" refers to the precipitation of calcium and carbonate ions from a solution, either by precipitation after the reaction of carbon dioxide and calcium hydroxide in an aqueous environment, such as CaCl ₂ and. It is a synthetic material usually obtained by precipitation of Na ₂ CO ₃ . A further possible method for producing PCC is the lime soda method or the Solvay method in which PCC is a by-product of ammonia production. Precipitated calcium carbonate has three major crystalline forms: calcite, aragonite and vaterite, and there are many different polymorphs (crystal habits) for each of these crystalline forms. Calcite has a trigonal structure, oblate triangular (S-PCC), rhombohedral (R-PCC), hexagonal prism, tabletop, colloidal (C-PCC), cubic. , And have typical crystal habits such as prismatics (P-PCC). Aragonite is not only an orthorhombic structure with typical crystal habits of twin hexagonal prismatic crystals, but also thin and elongated prismatics, curved blades, and steep pyramids. , Chisel-like (twin) crystals, branched trees and coral-like or insect-like shapes. Vaterite belongs to the hexagonal system. The obtained PCC slurry can be mechanically dehydrated and dried.

According to one embodiment of the invention, the precipitated calcium carbonate is preferably a mineral crystalline form of aragonite, vaterite or calcite, or a mixture thereof.

Precipitated calcium carbonate can be ground by the same means used for grinding natural calcium carbonate described above prior to treatment with carbon dioxide and at least one _H3O ⁺ ion donor.

According to one embodiment of the invention, the natural ground calcium carbonate or precipitated calcium carbonate is 0.05 to 10.0 μm, preferably 0.2 to 5.0 μm, more preferably 0.4 to 3.0 μm. Most preferably, it is in the form of particles having a weight median particle size _d50 of 0.6 to 1.2 μm, particularly 0.7 μm. According to a further embodiment of the present invention, the natural ground calcium carbonate or precipitated calcium carbonate is 0.15 to 55 μm, preferably 1 to 40 μm, more preferably 2 to 25 μm, most preferably 3 to 15 μm, and particularly 4 μm. It is a form of particles having a top-cut particle size d ₉₈ .

Naturally ground calcium carbonate and / or precipitated calcium carbonate can be used in a dry state or suspended in water. Preferably, the corresponding slurry is 1% to 90% by weight, more preferably 3% to 60% by weight, even more preferably 5% to 40% by weight, and most preferably 5% by weight, based on the weight of the slurry. It has a content of natural ground calcium carbonate or precipitated calcium carbonate in the range of 10% by weight to 25% by weight.

One or more H ₃ O ⁺ ion feeders used in the preparation of surface-reactive calcium carbonate is any strong acid, moderate strong acid or weak acid or a mixture thereof that produces H ₃ O ⁺ ions under the preparation conditions. Is. According to the present invention, the at least one H ₃ O ⁺ ion feeder can also be an acid salt that produces H ₃ O ⁺ ions under the conditions of preparation.

According to one embodiment, the at least one _H3O ⁺ ion feeder is a strong acid with a pK _a of 0 or less than 0 (0 or less) at 20 ° C.

According to another embodiment, the at least one _H3O ⁺ ion feeder is a moderately strong acid with _a pKa value of 0-2.5 at 20 ° C. If pK _a at 20 ° C. is 0 or less than 0 (0 or less), the acid is preferably selected from sulfuric acid, hydrochloric acid or mixtures thereof. When pK _a at 20 ° C. is 0-2.5, the H ₃ O ⁺ ion feeder is preferably selected from H ₂ SO ₃ , H ₃ PO ₄ , oxalic acid, or a mixture thereof. .. The at least one H ₃ O ⁺ ion feeder is at least partially neutralized with an acid salt, eg, a corresponding cation such as Li ⁺ , Na ⁺ or K ^{+ ,} HSO ₄ ^- or H ₂ PO _4- ,. Alternatively, it can be HPO 42 ₂ ^- at least partially neutralized with a corresponding cation such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ or Ca ²⁺ . The at least one _H3O ⁺ ion feeder may also be a mixture of one or more acids and one or more acid salts.

According to yet another embodiment, at least one _H3O ⁺ ion feeder is greater than 2.5 and less than 7 in relation to the ionization of initially available hydrogen when measured at 20 ° C. Alternatively, it is a weak acid having a pK _a value of 7 (7 or less) and having a corresponding anion capable of forming a water-soluble calcium salt. Subsequently, the hydrogen-containing salt has a pKa _a greater than 7 when measured at 20 ° C. in relation to its initially available hydrogen ionization, and the anion of that salt forms a water-soluble calcium salt. Where possible, at least one water-soluble salt is further supplied. According to a preferred embodiment, the weak acid has a pK _a value of more than 2.5 and up to 5 at 20 ° C., more preferably the weak acid is a group consisting of acetic acid, formic acid, propionic acid and mixtures thereof. Is selected from. An exemplary cation of the water-soluble salt is selected from the group consisting of potassium, sodium, lithium, and mixtures thereof. In a more preferred embodiment, the cation is sodium or potassium. The exemplary anion of the water-soluble salt is selected from the group consisting of phosphate anion, dihydrogen phosphate anion, monohydrogen phosphate anion, oxalate anion, silicate anion, mixtures thereof and hydrates thereof. To. In a more preferred embodiment, the anion is selected from the group consisting of a phosphate anion, a dihydrogen phosphate anion, a monohydrogen phosphate anion, a mixture thereof and a hydrate thereof. In the most preferred embodiment, the anion is selected from the group consisting of dihydrogen phosphate anion, monohydrogen phosphate anion, mixtures thereof and hydrates thereof. The addition of the water-soluble salt can be carried out by dropping or in one step. In the case of addition by dropping, such addition is preferably carried out within a time of 10 minutes or less. It is more preferable to add the salt in one step.

According to one embodiment of the invention, at least one _H3O ⁺ ion feeder is a group consisting of hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, oxalic acid, acetic acid, formic acid, and mixtures thereof. Is selected from. Preferably, the at _least one H3 O ⁺ ion feeder is at least partially neutralized with a corresponding cation such as hydrochloric acid, sulfuric acid, sulfite, phosphoric acid, oxalic acid; Li ⁺ , Na ⁺ or K ⁺ . H ₂ PO _{4-; selected from the group consisting of HPO 4} ^2- _; ^and mixtures thereof, at least partially neutralized with the corresponding cations such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ or Ca ²⁺ . More preferably, the at least one acid is selected from the group consisting of hydrochloric acid, sulfuric acid, sulfite, phosphoric acid, oxalic acid, or a mixture thereof, and most preferably the at least one _H3O ⁺ ion. The feeder is phosphate.

At least one _H3O ⁺ ion feeder can be added to the suspension as a concentrated solution or as a more diluted solution. Preferably, the molar ratio of _H3O ⁺ ion feeder to natural calcium carbonate or precipitated calcium carbonate is 0.01-4, more preferably 0.02-2, even more preferably 0.05-1, most preferably. Is 0.1 to 0.58.

Alternatively, it is possible to add the _H3O ⁺ ion feeder to the water prior to suspending the natural ground calcium carbonate or precipitated calcium carbonate.

In the next step, the natural ground calcium carbonate or precipitated calcium carbonate is treated with carbon dioxide. Carbon dioxide is automatically formed when a strong acid, such as sulfuric acid or hydrochloric acid, is used in the treatment of natural ground calcium carbonate or precipitated calcium carbonate with an _H3O ⁺ ion feeder. As an alternative or additionally, carbon dioxide can be supplied from an external source.

Treatment with _H3O ⁺ ion feeder and treatment with carbon dioxide can be performed simultaneously, if strong or moderately strong acids are used. For example, treatment with an _H3O ⁺ ion feeder can also be performed first with a moderately strong acid having _a pKa in the range 0-2.5 at 20 ° C., where carbon dioxide is in situ. It is formed and therefore the treatment with carbon dioxide will automatically be carried out simultaneously with the treatment with the _H3O ⁺ ion feeder, followed by additional treatment with carbon dioxide supplied from an external source. be able to.

Preferably, the concentration of carbon dioxide gas in the suspension is such that the ratio of (volume of suspension): (volume of CO ₂ gas) is 1: 0.05 to 1:20 in terms of volume, and even more. The concentration is preferably from 1: 0.05 to 1: 5.

In a preferred embodiment, the treatment step with the _H3O ⁺ ion feeder and / or the treatment step with carbon dioxide is repeated at least once, more preferably several times. According to one embodiment, the at least one _H3O ⁺ ion feeder is at least about 5 minutes, preferably at least about 10 minutes, typically about 10 to about 20 minutes, more preferably about 30 minutes. Minutes, even more preferably about 45 minutes, and sometimes over about 1 hour or more than 1 hour.

After treatment with _H3O ⁺ ion feeder and treatment with carbon dioxide, the pH of the aqueous suspension measured at 20 ° C. is, of course, greater than 6.0, preferably greater than 6.5, more. It preferably reaches a value greater than 7.0, even more preferably greater than 7.5, thereby greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, and even more. Surface-reactive natural calcium carbonate or surface-reactive precipitated calcium carbonate is preferably prepared as an aqueous suspension having a pH greater than 7.5.

For more details on the preparation of surface reaction natural ground calcium carbonate, see International Publication No. 00/39222 A1, International Publication No. 2004/0833116 A1, International Publication No. 2005/121257 A2, International Publication No. 2009/074492 A1. , European Patent Application Publication No. 2264 108 A1, European Patent Application Publication No. 2264 109 A1, and US Patent Application Publication No. 2004/0020410 A1. Incorporated in.

Similarly, surface reaction precipitated calcium carbonate is obtained. As will be understood in detail from WO 2009/074492 A1, surface reaction precipitated calcium carbonate solubilizes precipitated calcium carbonate in _H3O ⁺ ions and an aqueous medium to form a water-insoluble calcium salt. It can be obtained by contacting an anion that can be in an aqueous medium to form a slurry of surface reaction precipitated calcium carbonate, wherein the surface reaction precipitated calcium carbonate is on the surface of at least a portion of the precipitated calcium carbonate. Contains an insoluble, at least partially crystalline calcium salt of the anion formed in.

The solubilized calcium ion corresponds to an excess solubilized calcium ion with respect to the solubilized calcium ion naturally generated during the dissolution of the precipitated calcium carbonate by _H3O ⁺ ion. , The _H3O ⁺ ion is in the absence of any additional calcium ion or calcium ion source, solely in the form of a counterion to the anion, i.e., via the addition of the anion in the form of an acid or non-calcium acidic salt. Provided at.

The excess solubilized calcium ion is preferably an acid or neutral or acidic non-calcium that produces a soluble neutral or acidic calcium salt in situ, preferably by the addition of a soluble neutral or acidic calcium salt. Provided by the addition of salt.

The _H3O ⁺ ion is provided by the addition of an acid salt of an acid or the anion, or by the addition of an acid or acid salt that helps simultaneously provide all or part of the excess solubilized calcium ion. can do.

A more preferred embodiment of the preparation of surface reaction natural ground calcium carbonate or surface reaction precipitated calcium carbonate is a natural ground calcium carbonate or precipitated calcium carbonate of silicate, silica, aluminum hydroxide such as sodium aluminate or potassium aluminate. The reaction with the acid and / or the carbon dioxide in the presence of at least one compound selected from the group consisting of aluminates of alkaline earth metals, magnesium oxide, or mixtures thereof. Preferably, the at least one silicate is selected from aluminum silicate, calcium silicate, or alkaline earth metal silicate. These compounds can be added to an aqueous suspension containing natural calcium carbonate or precipitated calcium carbonate prior to the addition of the acid and / or the carbon dioxide.

Alternatively, of the silicate and / or silica and / or aluminum hydroxide and / or alkaline earth metal described above, although the reaction of natural ground calcium carbonate or precipitated calcium carbonate with acid and carbon dioxide has already begun. Alminates and / or magnesium oxide components can be added to an aqueous suspension of natural or precipitated calcium carbonate. Further on the preparation of surface reaction natural ground calcium carbonate or surface reaction precipitated calcium carbonate in the presence of an aluminate component of at least one silicate and / or silica and / or aluminum hydroxide and / or alkaline earth metal. Details are disclosed in International Publication No. 2004/083316 A1, and the contents of these documents are incorporated herein by reference.

The surface-reactive calcium carbonate can be left in suspension and optionally further stabilized with a dispersant. Conventional dispersants known to those of skill in the art can be used. Preferred dispersants are polyacrylic acid and / or carboxymethyl cellulose.

Alternatively, the dispersions described above can be dried, thereby containing little water in the form of granules or powders, that is, solid, i.e., dry or fluid. Calcium or surface reaction precipitated calcium carbonate can be obtained.

Surface-reactive calcium carbonate can have different particle morphologies, such as, for example, roses, golf balls and / or brains.

In a preferred embodiment, the surface-reactive calcium carbonate is 20 m ^{2 / g to 450 m 2 / g, more preferably 20 m 2 / g to 250 m 2 / g, more preferably 20 m 2 / g to} 450 m 2 / g, as measured by the ISO 9277 BET method using nitrogen. Has a specific surface area of 30 m ² / g to 160 m ² / g, most preferably 40 m ² / g to 150 m ² / g, and even more preferably 40 m ² / g to 140 m ² / g. In the sense of the present invention, this BET specific surface area is defined as the surface area of the particles divided by the mass of the particles. The specific surface area used here is measured by adsorption using BET isotherms (ISO 9277: 2010) and is defined in units of m ² / g.

According to one embodiment, the surface reaction calcium carbonate is 1 μm to 50 μm, preferably 1 μm to 45 μm, more preferably 2 μm to 30 μm, even more preferably 3 μm to 15 μm, most preferably 4 μm to 12 μm. Contains particles having a volume median particle size d ₅₀ (vol).

More preferably, the surface reaction calcium carbonate is less than 40.0 μm or 40.0 μm (40.0 μm or less), preferably less than 30.0 μm or 30.0 μm (30.0 μm or less), more preferably less than 25.0 μm or. Particle size d of 25.0 μm (25.0 μm or less), even more preferably less than 20.0 μm or 20.0 μm (20.0 μm or less), even more preferably less than 19.0 μm or 19.0 μm (19.0 μm or less). Includes particles with ₉₈ (vol). Preferably, the surface reaction calcium carbonate is 5.0 to 40 μm, preferably 6 to 30 μm, more preferably 7.0 to 25.0 μm, still more preferably 10.0 to 20.0 μm, and even more preferably 11.0. Includes particles with a particle size d ₉₈ (vol) in the range of ~ 19.0 μm.

The value d _x represents the diameter associated with the fact that x% of the particles have a diameter less than d _x . This means that the d ₉₈ value means that 98% of all particles have a particle size smaller than this value. The d ₉₈ value is also defined as a “top cut”. The _dx value can be given in volume percent or weight percent. Therefore, the d ₅₀ (wt) value means the weight median particle size, that is, 50% by weight of all particles is smaller than this particle size, and the d ₅₀ (vol) value is the volume median particle size, that is, This means that 50% by volume of the total particles are smaller than this particle size.

The volume median particle size _d50 was determined using the Malvern Mastersizer 2000 Laser Diffraction system. A d ₅₀ or d ₉₈ value measured using the Malvern Mastersizer 2000 Laser Diffraction System means a diameter value such that 50% by volume or 98% by volume of the particles each has a diameter less than this value. The raw data obtained by the measurement is analyzed using Mie theory with a particle index of refraction of 1.57 and an absorption coefficient of 0.005.

The weight median particle size is measured by the sedimentation method, which is an analysis method of sedimentation behavior in a gravity field. This measurement is made using the Sedigraph ^TM 5100 or 5120 of the Micromeritics Instrument Corporation. This method and this device are known to those of skill in the art and are commonly used to determine the particle size of fillers and pigments. This measurement is performed in a 0.1 wt% Na ₄ P ₂ O ₇ aqueous solution. The sample is dispersed using a high speed stirrer and sonicated.

This process and equipment are known to those of skill in the art and are commonly used to determine the particle size of fillers and pigments.

The specific pore volume is mercury infusion using a Micromeritics Autopore V 9620 mercury porosimeter with a maximum applicable pressure of mercury of 414 MPa (60,000 psi), which is equivalent to a Laplace throttle diameter of 0.004 μm (~ nm). It is measured using the formula porosimeter measurement method. The equilibrium time used at each pressure step is 20 seconds. The sample material is sealed in a 5 cm ³ powder penetration meter chamber for analysis. The data are corrected for mercury compression, penetration meter expansion and sample material compression using the software Pore-Comp (Gane, PAC, Kettle, JP, Mathews, GP. ..

The total pore volume found in the integrated intrusion data can be divided into two regions with intrusion data ranging from 214 μm to about 1-4 μm, which indicates the coarse packing of the sample between any agglutinating structures that contribute strongly. Below these diameters, there is fine interparticle packing of the particles themselves. If the particle also has intraparticle pores, this region is bimodal and mercury is in the pores finer than the mode turning point, i.e. the pores finer than the bimodal inflection. The inflection specific pore volume is defined here as the intrusion specific pore volume. The sum of these three regions gives the overall pore volume of the sum of the powder, but is strongly dependent on the sedimentation of the powder in the original sample compression / coarse pore end distribution.

By taking the first derivative of the integrated penetration curve, the pore diameter distribution based on the equivalent of Laplace diameter, which inevitably includes pore shielding, becomes clear. These derivative curves clearly show the pore structure region of the coarse agglomerates, the interparticle pore region and, if present, the intraparticle pore region. Once the range of the intra-particle pore diameter is known, the remaining inter-particle pore volume and inter-aggregate pore volume are subtracted from the total pore volume and used as the pore volume per unit mass (as the specific pore volume) inside. The desired pore volume can be obtained for the pores only. Of course, the same deduction principle also applies when separating any other pore size region of interest.

Preferably, the surface-reactive calcium carbonate is 0.15 cm ³ / g to 1.35 cm ³ / g, preferably 0.30 cm ³ / g to 1.30 cm ³ , calculated from the measurement results with a mercury intrusion porosimeter. It has an intraparticle penetration ratio pore volume of / g, most preferably in the range of 0.40 cm ³ / g to 1.25 cm ³ / g.

The pore size of the surface reaction calcium carbonate is determined by the measurement result with a mercury intrusion type porosimeter and is in the range of 4 to 500 nm, more preferably in the range of 20 to 80 nm, particularly in the range of 30 to 70 nm, for example, 50 nm. Is.

The pore diameter in the particles of the surface reaction calcium carbonate is determined by the measurement result with a mercury intrusion type porosimeter, and is preferably in the range of 0.004 to 1.6 μm, more preferably in the range of 0.005 to 1.3 μm. Particularly preferably, it is in the range of 0.006 to 1.15 μm, most preferably in the range of 0.007 to 1.0 μm, for example, in the range of 0.004 to 0.51 μm.

According to a preferred embodiment, the intra-particle pores and / or inter-particle pores of the surface-reactive calcium carbonate obtained in step (a) are hollow, and therefore the surface-reactive calcium carbonate in step (a) is not carried. Yes (active ingredient is not carried).

The surface reaction calcium carbonate can be in the form of fine powder (dust) or powder (powder), preferably in the form of powder.

Method Step (b)
In step (b) of the method of the invention, at least one active ingredient and / or its inert precursor is provided.

In one embodiment of the invention, the at least one active ingredient and / or its inert precursor comprises one active ingredient and / or its inert precursor, preferably one active ingredient and / or. It consists of its inert precursor. Alternatively, the at least one active ingredient and / or its inert precursor comprises two or more active ingredients and / or its inert precursor, preferably two or more active ingredients and / Or its inactive precursor. For example, the at least one active ingredient and / or its inert precursor comprises two or three active ingredients and / or its inert precursor, preferably two or three active ingredients and / or its non-active ingredient. It consists of an active precursor.

Preferably, the at least one active ingredient and / or its Inactive Precursor comprises one Active Ingredient or its Inactive Precursor, preferably consisting of one Active Ingredient or its Inactive Precursor.

In the sense of the present invention, the term "active ingredient" refers to a substance having a specific effect in an organism and causing a specific reaction in humans, animals, microorganisms and / or plants. Point to.

It is understood that the at least one active ingredient and / or its inert precursor can be a chiral compound. Thus, the at least one active ingredient and / or its inert precursor comprises (R) -enantiomer, (S) -enantiomer, and mixtures thereof, such as racemic mixtures.

In addition or as an alternative, the at least one active ingredient and / or its inert precursor can be an heterogeneous compound. Thus, the at least one active ingredient and / or its inert precursor comprises (Z) -isomer, (E) -isomer, and mixtures thereof.

For example, the at least one active ingredient and / or its inert precursor may be a fragrance, a flavor, an herb extract, a fruit extract, a nutrient, a trace mineral, a repellent, a food, a cosmetic, a flame retardant, an enzyme, or a high. Includes molecules, pesticides, fertilizers, preservatives, antioxidants, reactive chemicals, synthetically-originating, semi-synthetic or naturally occurring pharmaceutical activators or pharmaceutical inactive precursors, and mixtures thereof. Selected from the group.

The fragrance is preferably an alcohol, aldehyde and / or ketone having a molecular weight of at least about 100 g / mol, which is useful for imparting aroma, aroma, essence or odor alone or in combination with other fragrances. For example, the fragrances are 2,4-dimethyl-3-cyclohexene-1-methanol (floralol), 2,4-dimethylcyclohexanemethanol (dihydrofloralol), 5,6-dimethyl-1-methylethenylbicyclo [2]. .2.1] Hept-5-en-2-methanol (arbozole), α, α-4-trimethyl-3-cyclohexene-1-methanol (α-terpineol), 2,4,6-trimethyl-3-cyclohexene -1-Methanol (isocyclogeraniol), 4- (1-methylethyl) cyclohexanemethanol (mayor), α-3,3-trimethyl-2-norbornanethanol, 1,1-dimethyl-1- (4-methylcyclohexyl) 3-Enyl) methanol, 2-phenylethanol, 2-cyclohexylethanol, 2- (o-methylphenyl) ethanol, 2- (m-methylphenyl) ethanol, 2- (p-methylphenyl) ethanol, 6, 6-Dimethylbicyclo [3.1.1] Hept-2-en-2-ethanol (Nopol), 2- (4-methylphenoxy) ethanol, 3,3-dimethyl-Δ2 ^- β-norbornan ethanol (patchomint) , 2-Methyl-2-cyclohexylethanol, 1- (4-isopropylcyclohexyl) ethanol, 1-phenylethanol, 1,1-dimethyl-2-phenylethanol, 1,1-dimethyl-2- (4-methylphenyl) Ethanol, 1-phenylpropanol, 3-phenylpropanol, 2-phenylpropanol (hydrotropic alcohol), 2- (cyclododecyl) propan-1-ol (hydroxyamblanc), 2,2-dimethyl-3- (3-) Methylphenyl) -Propane-1-ol (Majantol), 2-Methyl-3-phenylpropanol, 3-Phenyl-2-Propen-1-ol (Synamyl alcohol), 2-Methyl-3-phenyl-2 -Propen-1-ol (methylcinnamyl alcohol), α-n-pentyl-3-phenyl-2-propen-1-ol (α-amyl-cinnamyl alcohol), ethyl-3-hydroxy-3-phenylpropio Nate, 2- (4-methylphenyl) -2-propanol, 3- (4-methylcyclohexa-3-ene) butanol, 2-methyl-4- (2,2,3-trimethyl-3-cyclopenten-1) -Il) Butanol, 2-ethyl-4- (2,) 2,3-trimethyl-Cyclopent-3-enyl) -2-buten-1-ol, 3-methyl-2-buten-1-ol (Prenol), 2-methyl-4- (2,2,3-trimethyl) -3-Cyclopenten-1-yl) -2-buten-1-ol, ethyl 3-hydroxybutyrate, 4-phenyl-3-buten-2-ol, 2-methyl-4-phenylbutane-2-ol, 4 -(4-Hydroxyphenyl) butane-2-one, 4- (4-hydroxy-3-methoxyphenyl) -butane-2-one, 3-methyl-pentanol, 3-methyl-3-penten-1-ol , 1- (2-propenyl) cyclopentane-1-ol (Prinol), 2-methyl-4-phenylpentanol (Pamplefluur), 3-methyl-5-phenylpentanol (phenoxanol), 2-methyl- 5-Phenylpentanol, 2-Methyl-5- (2,3-dimethyltricyclo [2.2.1.0 ^2,6 ] hept-3-yl) -2-penten-1-ol (Santalol) , 4-Methyl-1-phenyl-2-pentanol, 5- (2,2,3-trimethyl-3-cyclopentenyl) -3-methylpentane-2-ol (sandalore), (1-methyl-bicyclo [ 2.1.1] Hepten-2-yl) -2-methylpent-1-en-3-ol, 3-methyl-1-phenylpentan-3-ol, 1,2-dimethyl-3- (1-methylethenyl) ) Cyclopentane-1-ol, 2-isopropyl-5-methyl-2-hexenol, cis-3-hexene-1-ol, trans-2-hexen-1-ol, 2-isopropenyl-4-methyl-4 -Hexen-1-ol, 2-ethyl-2-prenyl-3-hexenol, 1-hydroxymethyl-4-iso-propenyl-1-cyclohexene (dihydrocuminyl alcohol), 1-methyl-4-iso Propenylcyclohexa-6-en-2-ol (carbenol), 6-methyl-3-isopropenylcyclohexane-1-ol (dihydrocarbole), 1-methyl-4-iso-propenylcyclohexane-3-ol, 4 -Isopropyl-1-methylcyclohexane-3-ol, 4-tert-butylcyclohexanol, 2-tert-butylcyclohexanol, 2-tert-butyl-4-methylcyclohexanol (rotanol), 4 -Isopropyl-cyclohexanol, 4-methyl-1- (1-methylethyl) -3-cyclohexene-1-ol, 2- (5,6,6-trimethyl-2-norbornyl) cyclohexanol, isobornylcyclohexanol , 3,3,5-trimethylcyclohexanol, 1-methyl-4-isopropylcyclohexane-3-ol, 1-methyl-4-isopropylcyclohexane-8-ol (dihydroterpineol), 1,2-dimethyl-3-( 1-Methylethyl) Cyclohexane-1-ol, Heptanol, 2,4-dimethylheptane-1-ol, 6-Heptyl-5-heptene-2-ol (isorinalol), 2,4-dimethyl-2,6- Heptandienol, 6,6-dimethyl-2-oxymethyl-bicyclo [3.1.1] hept-2-ene (myrtenol), 4-methyl-2,4-heptadiene-1-ol, 3,4 5,6,6-Pentamethyl-2-heptanol, 3,6-dimethyl-3-vinyl-5-heptene-2-ol, 6,6-dimethyl-3-hydroxy-2-methylenebicyclo [3.1.1 ] Heptene, 1,7,7-trimethylbicyclo [2.2.1] heptane-2-ol, 2,6-dimethylheptane-2-ol (dimethol), 2,6,6-trimethylbicyclo [1.3] .3] Heptane-2-ol, octanol, 2-octanol, 2-methyloctane-2-ol, 2-methyl-6-methylene-7-octen-2-ol (milsenol), 7-methyloctane-1- All, 3,7-dimethyl-6-octanol, 3,7-dimethyl-7-octanol, 3,7-dimethyl-6-octene-1-ol (citronellol), 3,7-dimethyl-2,6-octadien -1-ol (geraniol), 3,7-dimethyl-2,6-octadien-1-ol (nerol), 3,7-dimethyl-7-methoxyoctane-2-ol (osylol), 3,7-dimethyl -1,6-octadien-1-ol (linalol), 3,7-dimethyloctane-1-ol (pelargol), 3,7-dimethyloctane-3-ol (tetrahydrolinalol), 2,4-octadien-1 -Ol, 3,7-dimethyl-6-octene-3-ol (dihydrorinalol), 2,6-dimethyl-7-octene-2-ol (dihydromilsenol), 2,6-dimethyl-5,7 -O Kutadiene-2-ol, 4,7-dimethyl-4-vinyl-6-octen-3-ol, 3-methyloctane-3-ol, 2,6-dimethyloctane-2-ol, 2,6-dimethyloctane -3-ol, 3,6-dimethyloctane-3-ol, 2,6-dimethyl-7-octen-2-ol, 2,6-dimethyl-3,5-octadien-2-ol (Muguol), 3 -Methyl-1-octen-3-ol, 7-hydroxy-3,7-dimethyloctanal, 3-nonanol, 2,6-nonadien-1-ol, cis-6-nonen-1-ol, 6,8 -Dimethylnonan-2-ol, 3- (hydroxymethyl) -2-nonanone, 2-nonen-1-ol, 2,4-nonadien-1-ol, 3,7-dimethyl-1,6-nonadien-3 -All, decanol, 9-decenol, 2-benzyl-m-dioxa-5-ol, 2-decene-1-ol, 2,4-decadien-1-ol, 4-methyl-3-decene-5-ol , 3,7,9-trimethyl-1,6-decadien-3-ol (isobutyllinalol), undecanol, 2-undecene-1-ol, 10-undecene-1-ol, 2-dodecene-1-ol, 2 , 4-Dodecadien-1-ol, 2,7,11-trimethyl-2,6,10-Dodecatorien-1-ol (farnesol), 3,7,11-trimethyl-1,6,10-Dodecatorien- 3-ol (nerolidol), 3,7,11,15-tetramethylhexadeca-2-en-1-ol (phytol), 3,7,11,15-tetramethylhexadeca-1-en-3 -All (isophythol), benzyl alcohol, p-methoxybenzyl alcohol (anisyl alcohol), p-simene-7-ol (cuminyl alcohol), 4-methylbenzyl alcohol, 3,4-methylenedioxybenzyl alcohol, Methyl salicylate, benzyl salicylate, cis-3-hexenyl salicylate, n-pentyl salicylate, 2-phenylethyl salicylate, n-hexyl salicylate, 2-methyl-5-isopropylphenol, 4-ethyl-2-methoxyphenol, 4-allyl -2-Methylphenol (eugenol), 2-methoxy-4- (1-propenyl) phenol (isooigenol), 4-allyl-2,6-dimethoxyphenol, 4-tert-butylphenol , 2-ethoxy-4-methylphenol, 2-methyl-4-vinylphenol, 2-isopropyl-5-methylphenol (timole), pentyl-ortho-hydroxybenzoate, ethyl 2-hydroxy-benzoate, 2,4- Methyl dihydroxy-3,6-dimethylbenzoate, 3-hydroxy-5-methoxy-1-methylbenzene, 2-tert-butyl-4-methyl-1-hydroxybenzene, 1-ethoxy-2-hydroxy-4-propenyl Benzene, 4-hydroxytoluene, 4-hydroxy-3-methoxybenzaldehyde, 2-ethoxy-4-hydroxybenzaldehyde, decahydro-2-naphthol, 2,5,5-trimethyl-octahydro-2-naphthol, 1,3,3 -Trimethyl-2-norbornanol (fencor), 3a, 4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano-1H-inden-5-ol, 3a, 4,5 , 6,7,7a-Hexahydro-3,4-dimethyl-4,7-methano-1H-inden-5-ol, 2-methyl-2-vinyl-5- (1-hydroxy-1-methylethyl) tetrahydrofuran , Β-cariophyllene alcohol, vanillin, ethyl vanillin, cinnamaldehyde, benzaldehyde, phenylacetaldehyde, heptylaldehyde, octylaldehyde, decylaldehyde, undecylaldehyde, undecylenaldehyde, dodecylaldehyde, tridecylaldehyde, methylnonylaldehyde, didecylaldehyde, Anis aldehyde, citroneral, citronellyl oxyaldehyde, cyclamen aldehyde, α-hexyl cinnamaldehyde, hydroxy citroneral, α-methyl cinnam aldehyde, methyl nonyl acetaldehyde, propyl phenyl aldehyde, citral, perilla aldehyde, trill aldehyde, trill acetaldehyde, cumin You can choose from the group containing aldehydes, LILIAL®, salicylaldehyde, α-amylcinnamaldehyde and heliotropin, and mixtures thereof.

Various essential oils, herbal extracts and / or fruit extracts can also be used, preferably those with various medicinal or nutritional supplementary properties. Essential oils, herbal extracts and / or fruit extracts are generally extracts or aromatic plants, plant parts, fruits, or fruit parts that can be used as pharmaceuticals or for flavoring agents. .. Suitable herbal and / or fruit extracts can be used alone or in various mixtures.

Commonly used essential oils, herbal extracts and / or fruit extracts are Echinacea, Goldenseal, Calendula, Rosemary, Thyme, Hippo, Aloe, Akanegusa, Grapefruit seed extract, Black Kohosh, Ginseng, Includes galana, cranberry, ginkgo, rosemary, evening primrose oil, goldenseal bark, green tea, mao, maca, bilberry, lutein, ginger, eugenol-containing oil, and combinations thereof.

Various nutrients can be used, including virtually any vitamin, mineral, and / or phytochemical. For example, Vitamin A, Vitamin B1, Vitamin B6, Vitamin 12, Vitamin B2, Vitamin B6, Vitamin D, Vitamin E, ie tocopherols, vitamin K, thiamine, isoflavones, biotin, folic acid, niacin, pantothenic acid, Q10, α- Lipoic acid, dihydrolipoic acid, curcumin, xanthophils, β-cryptoxanthin, lycopene, lutein, zeaxanthin, astaxanthin, β-carotene, carotene, carotenoid mixture, polyphenols, flavonoids, sodium, potassium, calcium, magnesium, sulfur, chlorine, choline , And / or phytochemicals such as carotenoids, chlorophylls, chlorophyllins, dietary fibers, flavonoids, anthocyanins, cyanidins, delphinidins, malvidins, pelargonidins, peonidins, petunidins, flavonols, catechins, epicatechins, epigalolcatechins, epigalols. Catechin gallate, theaflavin, thealvidin, proanthocyanins, flavonols, kelcetin, chemperol, mylicetin, isoflavones, flavonon shesperetin, naringenin, eriodictrol, tangeretin, flavones, apigenin, luteolin, lignans, plant estrogen, resveratrol, Isoflavones, catechins, genisteins, glyciteins, soy isoflavones, and mixtures thereof can be used. Examples of nutrients that can be used as active ingredients are U.S. Patent Application Publication No. 2003/015723 Al, U.S. Patent Application Publication No. 2003/206993 A1, and U.S. Patent Application Publication No. 2003/0099741 Al. The contents of these documents are incorporated herein by reference in their entirety for all purposes.

In one embodiment, trace minerals such as manganese, zinc, copper, fluorine, molybdenum, iodine, cobalt, chromium, selenium, phosphorus, and combinations thereof can be used.

Enzymes include, but are not limited to, coenzyme Q10, pepsin, phytase, trypsin, lipase, protease, cellulase, lactase, and combinations thereof. Macromolecules are preferably known proteins, antibodies, receptors, carriers, polypeptides, peptides, probiotics or lipids.

The pesticides are preferably any known herbicide, pesticide, insect growth regulator, anti-nematode, white ant pesticide, soft animal pesticide, fish pesticide, bird pesticide, rodent pesticide, predatory animal pesticide. Agents, fungicides, pesticides, animal repellents, antibacterial agents, fungicides, disinfectants (antibacterial activators) and cleaning agents, which are known to those skilled in the art.

It should be noted that the preservative can be any such compound known to those of skill in the art. For example, preservatives include phenoxyethanol, ethylhexylglycerin, parabens (eg, methylparaben, ethylparaben, propylparaben, butylparaben and mixtures thereof), benzalconium chloride, butanol chloride, benzyl alcohol, cetylpyridinium chloride, tartaric acid, lactic acid, Includes, but is not limited to, malic acid, acetic acid, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate and mixtures thereof.

Antioxidants are preferably butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), gallate, carotinoids, polyphenols (eg, resveratrol, flavonoids and mixtures thereof), polyphenol derivatives, tocopherols and salts thereof. It is selected from the group containing beta-carotene, ubiquinone, tocotrienol, dihydrokercetin, naturally occurring antioxidants and mixtures thereof. In the case of naturally occurring antioxidants, such antioxidants are, for example, conifer extract, Pinus pinaster (Pinus pinaster) bark extract (eg, Pycnogenol from Holphag, Switzerland). And / or can be an embrica officinalis fruit extract (eg, Saberry® from Sabinsa Corporation, Germany).

The pharmaceutically active agent or pharmaceutically inactive precursor thereof is preferably selected from the group comprising synthetic, semi-synthetic or naturally-origin pharmaceutically active agents or pharmaceutically inactive precursors thereof, and combinations thereof. Will be done.

Thus, pharmaceutically active agents refer to synthetic, semi-synthetic or naturally occurring pharmaceutically active agents and combinations thereof. Further, the pharmaceutically inactive precursor of a pharmaceutically active agent refers to a synthetically-originating, semi-synthetic or naturally-originating pharmaceutically inactive precursor and a combination thereof, which is activated at a later stage. , Each pharmaceutical activator.

The conversion or activation of such pharmaceutically active or inert prodrugs is known to those of skill in the art and is commonly utilized, such as by pH-mediated or enzyme-mediated activation, eg, stomach and. / Or conversion and activation in the gastrointestinal tract.

It is within the understanding of those skilled in the art that the above activation method has mere exemplary properties and is not intended to be an activation method having limited properties.

It should be noted that the pharmaceutically active agent or pharmaceutically inactive precursor thereof can be any such compound known to those of skill in the art.

Thus, pharmaceutically active agents include any compound that, when administered to humans and / or animals, confer prophylactic and / or therapeutic properties. Examples include, but are not limited to, pharmaceutical activators, therapeutic activators, veterinary activators, dietary supplements and growth regulators and the corresponding active or inert precursors thereof. ..

For example, the pharmaceutically active agent or its pharmaceutically inactive precursor can be an anti-inflammatory agent. Such agents may include, but are not limited to, non-steroidal anti-inflammatory drugs such as NSAIDs such as propionic acid derivatives; acetic acid derivatives; phenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. All of these NSAIDs are fully described in US Pat. No. 4,985,459 of Sunshine et al., And the entire description of such NSAIDs is incorporated herein by reference in its entirety. Examples of useful NSAIDs are acetylsalicylic acid, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pillprofen, carprofen, oxaprozin, pranoprofen, microprofen. , Thioxaprofen, suprofen, aluminoprofen, thiaprofenic acid, flurbiprofen, ibuprofenic acid, and mixtures thereof.

Steroidal anti-inflammatory agents such as hydrocortisone and COX-2 (cyclooxygenase-2) inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib, etoricoxib or mixtures thereof are also useful. Mixtures with any of the above anti-inflammatory agents can also be used.

Other materials that can be used as a pharmaceutically active agent or pharmaceutically inactive precursor thereof include commonly known oral and throat products. These products include upper airway drugs (respiratory drugs) such as phenyleffrin, diphenhydramine, dextromethorphan, bromhexin and chlorpheniramine; gastrointestinal drugs such as famotidine, loperamide and simethicone; antifungal drugs such as myconazole nitrate; Antibiotics; as well as, but not limited to, analgesics such as ketoprofen and flurubiprofen.

The at least one pharmaceutically active agent or a pharmaceutically inactive precursor thereof may be an anti-tartar agent. A useful anti-tartar agent here is phosphate. Phosphates include pyrophosphates, polyphosphates, polyphosphonates and mixtures thereof. Of these, pyrophosphate is the most well-known phosphate used in dental care products. The pyrophosphate ion supplied to the tooth is derived from the pyrophosphate salt. Pyrophosphate salts useful in the drug delivery system of the present invention include two alkali metal pyrophosphate salts, four alkali metal pyrophosphate salts, and mixtures thereof. Disodium dihydrogen pyrophosphate (Na ₂ H ₂ P ₂ O ₇ ), tetrasodium pyrophosphate (Na ₄ P ₂ O ₇ ), and tetrapotassium pyrophosphate (K ₄ P ₂ O ₇ ) are non-hydrates thereof. And hydrate forms are preferred. Phosphates of anti-stone agents (anti-dental stone agents) include potassium pyrophosphate and sodium pyrophosphate; sodium tripolyphosphate; diphosphonates such as ethane-1-hydroxy-1,1-diphosphonate; 1-azacycloheptane-1, 1-Diphosphonate; Linear alkyl diphosphonate; Linear carboxylic acid and sodium citrate and zinc citrate are included.

The pharmaceutically active agent or the pharmaceutically inactive precursor thereof can be selected from sodium metabisulfite, butylhydroxytoluene and butylated hydroxyanisole.

The pharmaceutically active agent or its pharmaceutically inactive precursor can also be selected from: ephedrine, magaldrate, pseudoephedrine, sildenafil, xylocaine, benzalkonium chloride, caffeine, phenilefurin, ampefuramon, auristat, Sibutramine, Acetaminophen, Aspirin, Glytazone, Metformin, Chlorpromazine, Dimenhydrinate, Domperidone, Meclodin, Metclopramid, Odancetron, Prednisolone, Promethazine, Acrivastin, Cetizidine, Cinnaridine, Cremastin, Cyclydin, Desloratadin Nate, Evastin, Fexophenazine, Ibuprofen, Levorevoprolysine, Loratazine, Meclodin, Misorastine, Promethazine, Myconazole, Chlorhexidinediacetate, Fluoride, Decapeptide KSL, Aluminum Fluoride, Aminochelate Calcium, Ammonium Fluoride, Ammonium Phosphorus Fluoride , Ammonium monofluorophosphate, calcium fluoride, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium monofluorophosphate, calcium carbonate, carbamide, cetylpyridinium chloride, chlorhexidine, chlorhexidine digluconate, chlorhexidine chloride, chlorhexidine diacetate, CPP Casein phosphopeptide, hexetidine, octadecenylammonium fluoride, potassium fluorosilicate, potassium chloride, potassium monofluorophosphate, sodium hydrogencarbonate, sodium carbonate, sodium fluoride, sodium fluorosilicate, sodium monofluorophosphate, Sodium tripolyphosphate, stannous fluoride, stearyltrihydroxyethylpropylenediamine dihydrofluoride, strontium chloride, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, alginic acid, aluminum hydroxide, carbonic acid Sodium hydrogen hydrogen, sildenafil, tadalafil, valdenafil, yohinbin, simethidine, nizatidine, lanitidin, acetylsalicylic acid, clopidogrel, acetylcysteine, bromhexin, codeine, dextrometholphan, diphenhydramine, noscapine, phenylpropanolamine, vitamin D, simvastatin, bi Sakodil, lactitol, lactulose, magnesium oxide, sodium picosulfate, senaglycoside, benzocaine, lidocaine, tetrakine, almotriptan, eletriptan, naratriptan, lysatriptan, sumatriptan, solmitriptan, calcium, chromium, copper, iodine, Magnesium, manganese, molybdenum, phosphorus, selenium, zinc, chloramine, hydrogen peroxide, metronidazole, triptan acetonide, benzethonium chloride, cetylpyridinium chloride, chlorhexidine, fluoride, lidocaine, ampicillin, myconazole, nistatin, fish oil, ginkgo, ginseng, Ginger, purple cornflower, sawtooth palm, cetilidine, levosetilidine, loratazine, diclofenac, flurbiprofen, acrivastimpsoid efedrin, loratazimpsoid efedrin, glucosamine, hyaluronic acid, decapeptide KSL-W, decapeptide KSL, resveratrol Prostor, bupropion, ondancetron hydrochloride, esomeprazole, lansoprazole, omeprazole, pantoprazole, labeprazole, bacteria, etc., loperamide, simethicone, acetylsalicylic acid and others, scralfate, clotrimazole, fluconazole, itraconazole, ketoconazole, terbinazole, Alloprinol, Provenecid, Atrubastatin, Flurbiprofen, Robastatin, Nicotinic acid, Pravastatin, Losvastatin, Cymbastatin, Pyrocarpine, Naproxene, Allendronate, Ethidronate, Laroxyphene, Lysedronate, Benzodiazepine, Disulfyllam, Nartrexone, Buprenorfin, Codein, Dexitrophenyl , Hydromorphone, ketobemidone, ketoprofen, metadon, morphine, naproxen, nicomorphine, oxycodon, petidin, tramadol, amoxycillin, ampicillin, azithromycin, cyprofloxatin, clarisromycin, doxicyclin, erythromycin, fusidic acid, lymecycline, metro. Floxacin, offloxacin, oxytetracycline, phenoxymethylpenicillin, rifamycin, loxythromycin, sulfamethyzol, tetracycline, triptan, vancomycin, Acarbose, Glybenclamid, Glycladide, Glymepyride, Gripidide, Insulin, Repaglinide, Torbutamide, Osertamivir, Acyclovir, Famcyclovir, Pencyclovir, Balgancyclovir, Amropidine, Zyrthiazem, Ferrodipine, Nifedipine, Bellapamil, Finasteride, Minoxidein, Cocaine , Nartrexone, calcium antagonist, clonidine, ergotamine, β-blocker, asecrophenac, celecoxib, dexprofen, etdrac, indomethacin, ketoprofen, ketoconazole, lornoxicum, meroxycam, nabmeton, uloxycam, parecoxib, phenylbutazone, pyroxycam , Torphenamic acid, alipiprazole, chlorpromazine, chlorprothixene, clozapin, fulpentixol, flufenazine, haloperidol, lithium carbonate, lithium citrate, melperon, penfluridor, pericidin, perphenazine, pimodide, pipamperon, prochlorpera Gin, risperidone, thiorididine, fluconazole, itraconazole, ketoconazole, boriconazole, achen, benzodiazepine, hydroxyn, meprobamate, phenothiazine, aluminum aminoacetate, esomeprazole, famotidine, magnesium oxide, nizatide, omeprazole, pantoprazole, fluconazole, itraconazole. , Metronidazole, amphetamine, athenolol, bisoprol fumarate, metprolol, metroprolol, pindrol, propranolol, auranofin, and bendazac.

Further examples of useful pharmaceutical active agents or pharmaceutical inactive precursors thereof can include active ingredients selected from the group of therapeutic agents including: analgesics, anesthetics, antipyretics, anti-inflammatory agents. Allergic drugs, anti-arrhythmic drugs, appetite suppressants, antifungal drugs, anti-inflammatory drugs, bronchial dilators, cardiovascular drugs, coronary artery dilators, brain dilators, peripheral vasodilators, anti-infective drugs, psychiatric drugs, anti-manipulative drugs Agents, stimulants, antihistamines, constipation agents, blood-thinning agents, gastrointestinal sedatives, sexual dysfunction agents, disinfectants, antidiarrhea agents, antiangiopathic agents, vasodilators, antihypertensive agents, vasocontractors, pieces Headache remedies, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, sedatives, antiemetics, antivomits, antispasmodics, neuromuscular drugs, hyperglycemia And hypoglycemic drugs, thyroid and antithyroid drugs, diuretics, antispasmodics, uterine relaxation drugs, antiobesity drugs, appetite suppressants, antispasmodics, anabolic drugs, erythroid forming agents, antiasthotic drugs, sputum drugs, cough suppressants, mucus Dissolving drugs, anti-urinary drugs, dental vehicles, mouth odor removers, anti-acid agents, anti-diuretic drugs, anti-drugs, beta receptor blockers, tooth whitening agents, enzymes, coenzymes, proteins, energy boosters, fibers, Probiotics, prebiotics, NSAIDs, antitussives, decongestants, antihistamines, sputum, antidiarrhea, hydrogen antagonists, proton pump inhibitors, general non-selective central nervous system (CNS) inhibitors , General non-selective central nervous system (CNS) stimulants, selective central nervous system (CNS) function improving drugs, anti-Parkinson's disease drugs, drug analgesics, analgesic and antipyretic drugs, psychopharmacological drugs, and sexual dysfunction drugs ..

Examples of useful pharmaceutically active agents or pharmaceutically inactive precursors thereof can also include: casein glycomacropeptide (CGMP), triclosan, cetylpyridinium chloride, domiphen bromide, quaternary ammonium salt. , Zinc component, sanginalin, fluoride, alexidine, octonidin, EDTA, aspirin, acetaminophen, ibprofen, ketoprofen, diflunisal, phenoprofene calcium, naproxene, tolmethin sodium, indomethacin, benzonatete, caramiphen ediculate, menthol, Dextromethorphan hydrobromide, theobromine hydrochloride, clofendianol hydrochloride, pseudoephedrine hydrochloride, phenilefurin, phenylpropanolamine, pseudoephedrine sulfate, brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate , Dextromethorphan maleate, diphenhydramine hydrochloride, diphenpyrlide hydrochloride, azatazine maleate, diphenhydramine citrate, doxilamine succinate, promethazine hydrochloride, pyriramine maleate, triperene citrate, triprolidine hydrochloride, acrivastin, loratazine, brom Pseudoephedrine, dexbrompheniamine, guayphenesin, tocon, potassium iodide, terpine hydrate, loperamide, famotidine, lanitidine, omeprazole, lansoprazole, aliphatic alcohol, barbiturate, caffeine, strikinone, picrotoxin, pentylenetetrazole , Phenidantin, Penobarbital, Primidone, Carbamazepine, Etoscusmid, Metosuccimid, Fenceximide, Trimethadione, Diazepam, Benzodiazepine, Phenasemide, Phenetsurid, Acetazolamide, Sultium, Brom, Levodopa, Amantadin, Morphine Morphon, levofanol, codeine, hydrocodon, xicodon, nalolfin, naloxone, naltrexone, salicylate, phenylbutazone, indomethacin, phenacetin, chlorpromazine, mettrimeprazine, haloperidol, clozapine, reserpine, imipramine, tranylcipromin, pheneldin, lithium, Syldenafil citrate, tadalafil, and valdenafil CL. For example, eugenol can be used as an anesthetic.

Examples of useful pharmaceutical active agents or pharmaceutical inactive precursors thereof can include active ingredients selected from the following groups: ACE (angiotensin converting enzyme) inhibitors, anti-angiopathies, anti-arrhythmia. Drugs, anti-asthma drugs, anti-cholesterolemia drugs, analgesics, anesthetics, anti-spasmodic drugs, antidepressants, anti-diabetic drugs, anti-diarrhea drugs, antidote, anti-histamine drugs, antihypertensive drugs, anti-inflammatory drugs, anti-lipid drugs , Anti-manic drug, anti-vomiting drug, anti-stroke drug, anti-thyroid drug, anti-tumor drug, anti-viral drug, acne drug, alkaloid, amino acid drug, anti-tussifying drug, anti-urinary drug, anti-viral drug, anabolic drug, systemic and Non-systemic anti-infective drug, anti-neoplastic drug, anti-Parkinson's disease drug, anti-rheumatic drug, appetite stimulant, biological response regulator, blood regulator, bone metabolism regulator, cardiovascular drug, central nervous system stimulant , Cholinesterase inhibitors, contraceptives, decongestants, nutritional supplements, dopamine receptor agonists, endometriosis management drugs, enzymes, erectile dysfunction drugs such as sildenafil citrate currently sold as Viagra ^TM , infertility Remedies, gastrointestinal drugs, homeopathy remedies, hormones, hypercalcemia and hypocalcemia remedies, immunomodulators, immunosuppressants, migraine remedies, sickness relievers, muscle relaxation remedies, obesity remedies, osteoporosis Therapeutic agents, uterine contractions, parasympathomimetics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory medications, sedatives, quitting aids such as bromocryptin, sympathomimetics, tremor preparations, urine Road agents, vasodilators, laxatives, antioxidants, ion exchange resins, antipyretic agents, appetite suppressants, sputum expellants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary artery dilators, brain dilators, peripheral vasodilators , Antipsychotics, stimulants, antihypertensives, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, anti Vomiting drugs, anti-spasmodic drugs, neuromuscular drugs, hyperglycemic and hypoglycemic drugs, thyroid and anti-thyroid preparations, diuretics, antispasmodics, terrin-relaxing drugs, anti-obesity drugs, erythropoiesis drugs, anti-asthma drugs, cough suppressants, Mucolytic agents, DNA and recombinant drugs, and combinations thereof.

Examples of useful pharmaceutical active agents or pharmaceutical inactive precursors thereof considered can also include antacids, H2 antagonists and analgesics. For example, the dose of antacid can be prepared using the components calcium carbonate alone or in combination with magnesium hydroxide and / or aluminum hydroxide. In addition, antacids can be used in combination with H2 antagonists.

Analgesics include opiates (soothings) such as oxycontin ^TM and derivatives of opiates, ibuprofen, aspirin, acetaminophen, and combinations thereof, optionally containing caffeine.

Other useful pharmaceutical active agents or pharmaceutical inactive precursors thereof can include antidiarrheal agents such as ^ImmunoTM AD, antihistamines, antitussives, antitussives, vitamins and mouth odor removers. .. Here, the following are also intended to be used: anxiolytics such as Xanax ^TM ; antipsychotics such as Crozaril ^TM and Holdol ^TM ; ibuprofen, naproxen sodium, Voltaren ^TM and Rodine ^TM . Nonsteroidal anti-inflammatory drugs (NSAIDs); antihistamines such as Claritin ^TM , Hismanal ^TM , Relafen ^TM and Tabist ^TM ; antihypertensive agents such as Kytril ^TM and Cesamet ^TM ; bronchial dilators such as Bentolin ^TM and Proventel ^TM . Anti-depressants such as Prozac ^TM , Zoloft ^TM and Paxil ^TM ; anti-mitral pain drugs such as Imigra ^TM ; ACE inhibitors such as Vasotec ^TM , Capoten ^TM and Zestril ^TM ; anti-Alzheimer drugs such as Nicergline ^TM ; CaH antagonists such as Procardia ^TM , Adalat ^TM and Calan ^TM .

Common H2 antagonists intended for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifenthidine, roxatidine, pisatidine and aceroxatidine.

Acidic agents as active ingredients include, but are not limited to: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium carbonate, hydrogen carbonate. , Bismus aluminate, bismuth carbonate, bismuth carbonate, bismuth hypophagoic acid, bismuth nitrate, bismuth salicylate, calcium phosphate, citrate ion (acid or salt), aminoacetic acid, magnesium aluminate sulfate hydrate, magardrate, aluminokei Magnesium Acid, Magnesium Carbonate, Magnesium Glycinate, Magnesium Hydroxide, Magnesium Oxide, Magnesium Trisilicate, Milk Solids, First Aluminum Calcium Phosphate, Tricalcium Phosphate, Potassium Hydrogen Carbonate, Sodium Tartrate, Sodium Hydrogen Carbonate, Aluminum Nokei Magnesium acid, tartrate acid and salt.

In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof is an analgesic / anesthetic such as menthol, phenol, hexylresorcinol, benzokine, dichronin hydrochloride, benzyl alcohol, salicyl alcohol and combinations thereof. You can choose from. In some embodiments, the pharmaceutical active agent or pharmaceutical inactive precursor thereof can be selected from slippery elm bark, pectin, gelatin and viscous agents (analgesics) such as combinations thereof. In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof can be selected from bactericidal components such as cetylpyridinium chloride, domiphen bromide, decalinium chloride, eugenol and combinations thereof.

In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof is clofedanol hydrochloride, codeine, codeine phosphate, codeine sulfate, dextromethorphan, dextromethorphan hydrobromide, citric acid. You can choose from antitussive ingredients such as diphenhydramine and diphenhydramine hydrochloride and combinations thereof.

In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof can be selected from throat analgesics such as honey, propolis, aloe vera, glycerin, menthol and combinations thereof. In yet another embodiment, the pharmaceutically active agent or pharmaceutically inactive precursor thereof can be selected from cough medicines. Such cough suppressants fall into two categories: those that alter the texture and production of sputum, such as mucolytics and expectorants; and codeins (drug cough suppressants), antihistamines, dextromethorphan and Isoproterenol (a non-pharmaceutical antitussive) that suppresses the cough reflex.

In yet another embodiment, the pharmaceutically active agent or pharmaceutically inactive precursor thereof is from the group comprising codeine, dextromethorphan, dextrorphan, diphenhydramine, hydrocodone, noscapine, oxycodone, pentoxyberin and combinations thereof. You can choose. In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof is acrivastin, azatazine, bromphenindamine, clo (fi) heniramine, clemastine, cyproheptadine, dexbrompheniramine, dimenhydrinate, diphenhydramine, You can choose from antihistamines such as doxylamine, hydroxyzine, meclizine, phenindamine, phenyltroxamine, promethazine, pyriramine, tripereneamine, triprolidine and combinations thereof. In some embodiments, the pharmaceutically active agent or pharmaceutically inactive precursor thereof is selected from non-sedating antihistamines such as astemizole, cetirizine, ebastine, fexofenadine, loratidine, terfenadine and combinations thereof. Can be done.

For example, the at least one active ingredient and / or its inert precursor may be a fragrance, flavor, essential oil, pesticide, bactericide, pharmaceutically active agent or pharmaceutically inert precursor thereof, such as disinfectant. You can choose from agents and / or anesthetics and mixtures thereof. Most preferably, the at least one active ingredient and / or its inactive precursor is a pharmaceutically active agent or pharmaceutically inert precursor thereof, such as a disinfectant and / or an anesthetic, or a mixture thereof. You can choose from.

The at least one active ingredient and / or its inert precursor is preferably in liquid form.

In the sense of the present invention, the term "liquid" comprises the at least one active ingredient and / or its inactive precursor, or comprises the at least one active ingredient and / or its inactive precursor. Refers to a non-gaseous fluid composition, which is readily fluid at the pressure conditions and temperature at the time of use, i.e., at the temperature at which the method of the invention, preferably method step (c), is carried out. ..

The at least one active ingredient and / or its inert precursor can be used as provided in liquid form or in a solvent. When the at least one active ingredient and / or its inert precursor is solid at room temperature, the at least one active ingredient and / or its inert precursor may be a solution, a dispersion (eg, a nanodisperse). It is preferably provided in a (aqueous or organic) solvent to form an emulsion (eg, nanoemulsion) or suspension (eg, nanosuspension).

When the at least one active ingredient and / or its inert precursor is provided in a solvent, the solvent is preferably water, methanol, ethanol, n-butanol, isopropanol, n-propanol, n-octanol. , Acetone, dimethyl sulfoxide, dimethylformamide, methanol, vegetable oils and derivatives thereof, animal oils and derivatives thereof, molten fats and waxes, and mixtures thereof, more preferably the solvent is water, ethanol and /. Or acetone. Most preferably, the solvent is ethanol and / or acetone.

When the at least one active ingredient and / or its inert precursor is solid at room temperature, the at least one active ingredient and / or its inert precursor can also be provided in a molten state, ie. The at least one active ingredient and / or its inert precursor is preferably provided in a molten state when the melting temperature is 180 ° C. or lower, preferably 20 to 100 ° C.

When the at least one active ingredient and / or its inert precursor itself is a liquid, the at least one active ingredient and / or its inert precursor is preferably in the temperature range of 5-100 ° C. The liquid is preferably in the temperature range of 10 to 80 ° C, most preferably 10 to 40 ° C. For example, the at least one active ingredient and / or its inert precursor is preferably 10-80 ° C, most preferably 10- It is a liquid in the temperature range of 40 ° C.

In one embodiment, the at least one active ingredient and / or its inert precursor is dissolved in a solvent. That is, the at least one active ingredient and / or its inert precursor and the solvent form a system in which no solid separated in the solvent is observed and thus forms a "solution".

The term "suspension" refers to a system containing insoluble solids and solvents as well as any additional additives, where suspensions usually contain large amounts of solids and are therefore more than the solvent that forms the suspension. , More viscous and generally higher density. However, the term "substantially insoluble" does not exclude cases where at least a portion of a solid substance dissolves in water under certain conditions (eg, at elevated temperatures).

When the at least one active ingredient and / or its inert precursor is provided in the solvent, the solvent is, for example, after the method step (c) and before the method step (d), eg. It is preferably removed by evaporation.

Method Step (c)
In step (c) of the method of the present invention, the surface-reacted calcium carbonate is loaded with the at least one active ingredient and / or its inert precursor.

Preferably, the carrying step (c) involves spraying or dropping the at least one active ingredient and / or its inert precursor onto the surface-reactive calcium carbonate, and the at least one active ingredient on the surface-reactive calcium carbonate. And / or by mixing the inert precursor thereof in a suitable apparatus for uniform distribution.

Any suitable means known technically can be used for the purposes of the present invention. However, the carrying step (c) is preferably from the group comprising a fluidized bed dryer / granulator, a plow shear mixer, a vertical or horizontal mixer, a high shear or low shear mixer, and a high speed blender. Performed in the selected device.

It is preferable that the supported surface-reacted calcium carbonate obtained in the method step (c) has no agglomerates (aggregates). Therefore, the supported surface-reactive calcium carbonate obtained in the method step (c) is preferably sieved, for example, 1000 μm before the method step (d) is performed.

Alternatively, when the supported surface-reactive calcium carbonate obtained in the method step (c) contains a lump (aggregate), the lump can be subjected to the deagglomeration step. Preferably, the deagglomeration step is performed before the compression step (d). In one embodiment, the deagglomeration step is performed so as to obtain particles having a median particle size of less than 1000 μm.

In addition or as an alternative, the supported surface-reactive calcium carbonate obtained in method step (c) can be subjected to a drying step. Preferably, the drying step is performed before the compression step (d). In one embodiment, the drying step is carried out so as to obtain a freely flowing product.

Preferably, the carrier step (c) can be carried out over a wide temperature and / or pressure range. For example, the supporting step (c) is carried out under ambient pressure conditions, that is, under atmospheric pressure, at a temperature exceeding 0 ° C., for example, in the range of 3 to 180 ° C., preferably 10 to 100 ° C., and most preferably 10 to 40 ° C. , Can be carried out. Alternatively, the supporting step (c) can be carried out under reduced pressure (under vacuum) in a temperature range of 5 to 180 ° C., preferably 10 to 100 ° C., and most preferably 10 to 40 ° C.

The carrier temperature is preferably adjusted according to the at least one active ingredient and / or its inert precursor thereof being supported. That is, when the at least one active ingredient and / or its inert precursor is provided in a molten state, the carrier temperature is preferably at the melting point of the at least one active ingredient and / or its inert precursor. It is adjusted accordingly.

In one embodiment, the carrier step (c) is carried out under ambient temperature and pressure conditions, for example at room temperature and atmospheric pressure such as about 5 to 35 ° C, preferably 10 to 30 ° C, most preferably 15 to 25 ° C. Can be carried out at. Alternatively, the loading step (c) can be carried out at ambient temperature, for example at room temperature such as about 5 to 35 ° C., preferably 10 to 30 ° C., most preferably 15 to 25 ° C. and under reduced pressure (under vacuum). ..

Method Step (d)
According to the step (d) in the method of the present invention, the mixture obtained in the step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to obtain a compressed form.

The term "roller compression" refers to the process by which fine powder is placed between two counter-rotating rollers and compacted into compressed forms such as ribbons, needles and / or flakes. means.

For the purposes of the present invention, roller compression can be performed with any suitable roller compressor known to those of skill in the art. For example, roller compression can be performed using a Fitzpatrick® Chilsonator CCS220 roller compressor from the Fitzpatrick Company of the United States.

One requirement of the method of the present invention is that step (d) is carried out at a consolidation pressure in the range of 1-30 kN / cm. Preferably, the roller compression step (d) is carried out at a roller consolidation pressure in the range of 1 to 28 kN / cm, more preferably in the range of 1 to 20 kN / cm, most preferably in the range of 2 to 10 kN / cm.

In addition or as an alternative, the feed rate and / or roll rate during the roller compression step is such that the compressed form is 0.2-6 mm, preferably 0.3-3 mm, more preferably 0.4-1 mm thick. It can be adjusted to obtain the speed. For example, the supply rate or roll rate during the roller compression step (d) is such that the compressed form has a thickness of 0.4 to 0.8 mm, preferably 0.5 to 0.7 mm, and most preferably about 0.6 mm. It can be adjusted to obtain the speed. Alternatively, the feed rate and roll rate during the roller compression step (d) are 0.4-0.8 mm, preferably 0.5-0.7 mm, most preferably about 0.6 mm for the compressed form. It can be adjusted to obtain the thickness.

One advantage of the method of the invention is that the compression of the supported (post-supported) surface-reactive calcium carbonate is carried out in the absence of a compounding aid such as a binder and / or a disintegrant. Is what you can do.

Therefore, one specific requirement of the present invention is that the compressed form of the surface-reactive calcium carbonate obtained in the step (d) is the surface-reactive calcium carbonate in the step (a) and the step (b). Consists of the at least one active ingredient and / or its inert precursor thereof, i.e., the carried (post-supported) surface-reactive calcium carbonate.

Method Step (e)
According to the step (e) in the method of the present invention, the compressed form obtained in the step (d) is crushed into granules (fine particles).

Milling can be carried out in any conventional mill known to those of skill in the art. For example, grinding can be performed using FitzMill® from Fitzpatrick, USA.

For example, the granules obtained in step (e) have a median particle size of 10 to 3000 μm, preferably 50 to 1500 μm, and most preferably 80 to 1200 μm.

Arbitrary Method Step According to any step (f) in the method of the present invention, the granules obtained in step (e) are subjected to a step (f) of sieving with at least one mesh size.

Such sieving is performed using any conventional sieving means known to those of skill in the art. Sifting is done using one or more mesh sizes. Suitable mesh sizes are, but are not limited to, 180 μm, 250 μm, 355 μm, 500 μm and 710 μm, respectively.

The mixture thus screened, i.e., the resulting granules, is obtained by sieving with different mesh sizes, preferably obtained by sieving with mesh sizes of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm, respectively. It has a particle size of 180 to 710 μm. More preferably, by sequentially sieving with mesh sizes of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm and combining the sifted mixtures, granules having a particle size of less than 180 μm and a particle size of more than 710 μm are excluded. For example, it can be carried out using the Vibrating sieve tower (vibration sheave tower) of Vibro Retsch, Switzerland.

In one embodiment, sieving is performed using mesh sizes of 250 μm, 355 μm, 500 μm and 710 μm, in sequence.

The mixture thus screened, i.e., the resulting granules, is obtained by sieving with different mesh sizes, preferably obtained by sieving with mesh sizes of 250 μm, 355 μm, 500 μm and 710 μm, in order, 250- It has a particle size of 710 μm. More preferably, by sequentially sieving with mesh sizes of 250 μm, 355 μm, 500 μm and 710 μm and combining the sifted mixtures, granules having a particle size of less than 250 μm and a particle size of more than 710 μm are excluded. For example, it can be carried out using the Vibrating sieve tower (vibration sheave tower) of Vibro Retsch, Switzerland.

It is within the understanding of the present invention that other mesh sizes and combinations of other mesh sizes are also within the scope of the present invention.

In such an embodiment, the method for producing the administered formulation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) Crushing the compressed form of step (d) into granules; and (f) sieving the granules of step (e) by at least one mesh size;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

As already outlined above, the compressed form of the supported (post-supported) surface-reactive calcium carbonate obtained in step (d) is free of compounding aids such as binders and / or disintegrants. Manufactured in the presence.

However, the granules obtained in step (e) and / or the granules obtained in step (f) can be mixed with at least one compounding aid and / or at least one compounding aid. Can be coated with an agent.

Thus, in one embodiment, the method of the invention provides at least one compounding aid (b1), and the granules obtained in step (e) and / or step (if performed). The granules obtained in f) are mixed with at least one compounding aid of step (b1) and / or coated with at least one compounding aid of step (b1), a mixing and / or coating step (c1). ) Is further included. Preferably, in the mixing and / or coating step (c1), the granules obtained in step (f) are mixed with at least one compounding aid in step (b1) and / or at least one in step (b1). Cover with two compounding aids.

In the mixing and / or coating step (c1), the granules obtained in the step (e) and / or the granules obtained in the step (f), if performed, are mixed with at least one compounding aid and / or This can be done by mixing and / or coating in any order to form the coating.

For the purposes of the present invention, any suitable mixing and / or coating means known in the art can be used to carry out the mixing and / or coating step (c1). However, the mixing and / or coating step (c1) is a coating, such as, for example, a fluidized bed dryer / granulator, a plow shear mixer, a vertical or horizontal mixer, a high shear or low shear mixer, and a high speed blender. It is preferably performed in a machine (coater), a mixer and / or a blender.

The expression "at least one" compounding aid means that the compounding aid comprises one or more compounding aids.

According to one embodiment of the invention, the compounding aid comprises only one compounding aid. According to yet another embodiment of the invention, the compounding aid comprises two or more mixtures of compounding aids. For example, a compounding aid comprises a mixture of two or three compounding aids.

In one embodiment of the invention, the at least one compounding aid comprises only one compounding aid.

For example, the at least one compounding aid includes a disintegrant, a lubricant, an impact modifier, a plasticizer, a wax, a stabilizer, a pigment, a colorant, a flavoring agent, a flavoring agent, a flavoring agent, a sweetener, and a texture. It is selected from the group containing improvers, diluents, film-forming agents, adhesives, buffers, adsorbents, odor masking agents, and mixtures thereof.

It is within the understanding of those skilled in the art that the above compounding aids are merely exemplary properties and are not intended to be compounding aids with limited properties.

Preferably, the at least one compounding aid is a modified cellulose gum, insoluble crosslinked polyvinylpyrrolidone, starch glycolate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, N-vinyl-2-. Homopolymer of pyrrolidone, alkyl cellulose ester, hydroxyalkyl cellulose ester, carboxyalkyl cellulose ester, alginate, microcrystalline cellulose and its crystalline polymorph, ion exchange resin, gum, chitin, chitosan, clay, gellan gum, crosslinked polarcrylin copolymer, agar , Gelatin, dextrin, acrylic acid polymer, sodium carboxymethyl cellulose / calcium, hydroxypropylmethyl cellulose phthalate, shelac, or a disintegrant selected from the group comprising mixtures thereof.

Examples of suitable disintegrants are: Ac-Di-Sol®, FMC, USA (modified cellulose gum); Kollidon® CL, BASF, Germany (insoluble crosslinked polyvinylpyrrolidone); Vivastar. (Registered Trademarks), JRS, Germany (Sodium Starch Glycolate); MCC Polymorph II (MCC SANAQ Burst®), Pharmatrans Sanaq AG, Microcrystalline Cellulose as Standard Microcrystalline Cellulose (MCC) MCC SANAQ 102 Stable crystalline polymorph type II).

In one embodiment, the at least one compounding aid is a lubricant, particularly an internal lubricant and / or an external lubricant, preferably at least one external lubricant. Alternatively, the at least one compounding aid is at least one internal lubricant and an external lubricant.

The at least one internal lubricant is a fatty acid sorbitan ester and a polyoxyethoxylated hydrogenated castor oil (eg, a product sold under the trade name CREMOPHOR®), a block copolymer of ethylene oxide and propylene oxide (eg, a block copolymer of ethylene oxide and propylene oxide). For example, products sold under the trade names of PLURONIC® and POLOXAMER), polyoxyethylene fatty alcohol ether, polyoxyethylene sorbitan fatty acid ester, sorbitan ester of fatty acid and polyoxyethylene stearate ester, stearyl alcohol, dibehen. It can be selected from the group comprising acid glycerol, stearyl sodium fumarate, glycerol distearate and combinations thereof. Preferably, the at least one internal lubricant is stearyl fumarate.

The at least one external lubricant is lecithin, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, fatty acid salt, edible fatty acid mono and diglyceride mono and diacetyl tartrate acid ester, edible fatty acid mono and diglyceride citrate ester. , Saccharose ester of fatty acid, polyglycerol ester of fatty acid, polyglycerol ester of ester-exchanged castor oil acid (E476), sodium stearoyl lactate, magnesium stearate and / or calcium stearate, hydride vegetable oil, stearic acid, sodium lauryl sulfate, You can choose from the group containing magnesium lauryl sulfate, colloidal silica, talc and combinations thereof. Preferably, the at least one external lubricant is magnesium stearate and / or calcium stearate, more preferably magnesium stearate.

In one embodiment, the at least one compounding aid is a plasticizer. For example, the plasticizer is a group consisting of triethyl citrate (TEC), tributyl citrate (TBC), acetyltributyl citrate (ATBC), acetyltriethyl citrate (ATEC) and acetyltri-2-ethylhexyl citrate (ATEHC). It can be a citric acid-based plasticizer selected from.

According to a further embodiment, the at least one compounding aid is a diluent, a film-forming agent, an adhesive, a buffer, an adsorbent, a natural or synthetic flavoring agent, a natural or synthetic flavoring agent, a natural or synthetic coloring agent. , Natural or synthetic sweeteners, natural or synthetic odor masking agents, natural or synthetic flavor or taste masking agents, natural and / or synthetic texture improvers, and mixtures thereof.

Suitable natural or synthetic flavoring agents generally include one or more volatile compounds that are perceived by humans or other animals by the sense of smell, at very low concentrations.

Suitable natural or synthetic flavoring agents include mint such as peppermint; menthol, vanilla, cinnamon, various fruit flavors; individual or mixed essential oils such as timhol, eucalypto, menthol and methyl salicylate; allylpyrazines, methoxy. Includes pyrazine, 2-isobutyl-3-methoxypyrazines, acetyl-L-pyrazines, 2-acetoxypyrazines, aldehydes, alcohols, esters, ketones, pyrazines, phenols, terpenoids, and mixtures thereof. However, it is not limited to these.

The flavoring agent is generally used in an amount that varies depending on the individual flavor, and can be, for example, in an amount ranging from about 0.5% by weight to about 4% by weight of the final-administered formulation.

Suitable natural or synthetic colorants include titanium dioxide, flavone dyes, isoquinoline dyes, polyene dyes, pyran dyes, naphthoquinone dyes, quinones and anthraquinone dyes, chromene dyes, benzopyran dyes and indigoid dyes and indole dyes. Not limited to. Examples of these are caramel coloring, annatto, chlorophyllin, cochineal, betanin, turmeric, saffron, paprika, lycopene, pandan and winglet.

Suitable natural or synthetic sweeteners include xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch or corn syrup solids, and sugar alcohols (eg, sorbitol, xylitol, mannitol). And mixtures thereof); soluble artificial saccharin salts (ie, sodium or calcium salts of saccharin), cyclamate salts, water-soluble artificial sweeteners such as Acesulfam-K, and L-aspartame-phenylalanine methyl ester, Alitama®. Alternatively, it includes, but is not limited to, free acid forms of saccharin and aspartame-based sweeteners such as Neotama®.

In general, the amount of sweetener will vary depending on the desired amount of sweetener selected for the particular pharmaceutical composition.

Suitable natural and / or synthetic texture improvers include polyethylene oxide (PEO-1NF) (Lot. L20141017A provided by Sumitomo Seika Chemical Co., Ltd. (Osaka)); hydroxypropyl cellulose (L-HPC LH-11) (Shin-Etsu). Chemical Industry (Japan), Lot. 505200); Hydroxypropyl Ethyl Cellulose (Polyethylene E15 LV Premium EP), Lot. LD20012N23; Gum arabic, Pheur, Roth, Germany, Lot. 024208213; or Instant gum AA, Nexira, France; or combinations thereof, but not limited to these.

In one embodiment, the at least one compounding aid is from about 0.1% to about 10.0% by weight, preferably about 0%, based on the total weight of the surface-reacted calcium carbonate in step (a). It is supplied in a total amount of 3% by weight to about 5.0% by weight, more preferably about 0.5% by weight to about 2.5% by weight.

When the method of the present invention comprises providing at least one compounding aid, the method for producing the administered formulation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules; and (c1) at least one compounding aid is provided, and the granules obtained in step (e) are at least said. Mix with one compounding aid and / or coat with at least one compounding aid;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

When the method of the present invention further comprises sieving, the method for producing the administered preparation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules;
(F) Sieve the granules of step (e) by at least one mesh size; and (c1) provide at least one compounding aid and obtain in steps (e) and / or step (f). The granules obtained, preferably the granules obtained in step (f), are mixed with the at least one compounding aid and / or coated with the at least one compounding aid;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

In still any further embodiment, the method of the invention is to tablet the granules obtained in step (e) or, if done, the granules obtained in step (f), or obtained in step (e). Further comprising step (g), which fills the capsule with granules or, if performed, the granules obtained in step (f). If such a method comprises a mixing and / or coating step (c1), the step (g) can also be carried out by tablet molding the granules obtained in the step (c1).

In the sense of the present invention, "tablet molding (tablet formation)" refers to the process of compressing or molding a material into a tablet (tablet) form. Tablets can be of any form and size of any technically known. A "capsule" can be any type of capsule that is technically known. For example, the capsule can be a gelatin capsule or an HPMC (hydroxypropylmethylcellulose) capsule.

The step (g) is carried out at a compression pressure in the range of 0.1 to 100 kN. It should be noted that the compressive pressure used in step (g) depends on at least one particular active ingredient and / or its inert precursor provided in step (b). Therefore, one of ordinary skill in the art can adapt the compression pressure accordingly. Preferably, step (g) is carried out with a compression pressure in the range of 0.5-50 kN, most preferably a compression pressure in the range of 1-25 kN. For example, step (g) is carried out with a compressive force in the range of 1-10 kN, most preferably a compression pressure in the range of 2-8 kN.

Tablet molding can be performed using any conventional compressor known to those of skill in the art. For example, tablet molding can be performed using a tablet press such as the Fette 1200i tablet press from Fette Compacting GmbH in Germany.

Preferably, the tablet obtained in the tablet molding step (g) can be subjected to the final coating step. Such coating can be performed by conventional coating means well known in the art and known to those of skill in the art.

In this embodiment, the method for producing the administered preparation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules;
(F) Arbitrarily sift the granules of step (e) by at least one mesh size; and (g) the granules obtained in step (e) or, if done, the granules obtained in step (f). Tableting or filling the capsule with the granules obtained in step (e) or, if done, the granules obtained in step (f);
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

When the method of the present invention further comprises providing at least one compounding aid, the method for producing the administered formulation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules;
(C1) To provide at least one compounding aid, and to mix the granules obtained in step (e) with the at least one compounding aid and / or to coat with the at least one compounding aid. And (g) tableting the granules obtained in step (c1) or filling the capsules with the granules obtained in step (c1);
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

When the method of the present invention further comprises sieving, the method for producing the administered preparation comprises the following steps, preferably comprising the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules;
(F) Sieve the granules of step (e) or step (c1) by at least one mesh size;
(C1) The at least one compounding of the granules obtained in the step (e) and / or the step (f), preferably the granules obtained in the step (f), to provide at least one compounding aid. Mix with auxiliaries and / or coat with at least one of the compound auxiliaries; and (g) granules obtained in step (f) and / or step (c1), preferably obtained in step (c1). The resulting granules are tableted or filled with the granules obtained in step (f) and / or step (c1), preferably the granules obtained in step (c1);
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.

The pharmaceutical product obtained by the method of the present invention can be granules, tablets, mini-tablets, or capsules.

Therefore, in one embodiment, the invention is further directed to granules obtained by the methods defined herein. In another aspect, the invention is further directed to tablets and / or capsules obtained by the methods defined herein.

Thus, the pharmaceutical product can be prepared in a wide range of sizes, and fractions of different sizes can be separated by conventional means such as sieving.

In general, the administered formulation can have a weight median particle size of 0.1 to 20.0 mm, preferably 0.2 to 15.0 mm, more preferably 0.3 to 10.0 mm.

In view of the good results obtained, the invention is directed in another embodiment to the dosage product, preferably a tablet, mini-tablet or capsule obtained by the method of the invention.

Another embodiment is a pharmaceutical product, dietary supplement, pesticide, cosmetics, household product, food product, in the granules defined herein, or the tablet and / or capsule defined herein, or the dosage product defined herein. It is intended for use in packaging and personal care products.

According to a further aspect, pharmaceutical products, dietary supplements, pesticides, cosmetics, household products, including the granules defined herein, or the tablets and / or capsules defined herein, or the pharmaceutical products defined herein. Food, packaging, and personal care products are provided.

A further aspect is directed to the use of surface-reactive calcium carbonate in the methods defined herein.

When discussing the technical details of the method according to the invention, the definition of the method, the dosage product, the surface-reactive calcium carbonate, the at least one active ingredient and / or its inert precursor, the at least one. The above description is referred to with respect to the compounding aids and preferred embodiments thereof.

The following examples and tests illustrate the invention, but are not intended to limit the invention in any way.

Materials and methods
1. 1. Measuring method
The following measurement methods were used to determine the values of the given parameters in this example and the claims.

Material BET Specific Surface Area (SSA)
The BET specific surface area was measured by the ISO 9277 BET method using nitrogen after preparing the sample by heating at 250 ° C. for 30 minutes. Prior to such measurements, the samples were filtered, rinsed and dried in the oven at 110 ° C. for at least 12 hours.

Particle size distribution (% by volume of particles with a diameter smaller than x), _d50 value (volume median particle size) and _d98 value of the particle material:
The volume median particle size _d50 was measured using the Malvern Mastersizer 2000 Laser Diffraction System. The d50 or _d98 values measured using the Malvern Mastersizer 2000 Laser Diffraction System indicate that 50% or ₉₈ % by volume of the particles have a diameter less than this value, respectively. The raw data obtained by this measurement is analyzed using Mee theory with a particle index of refraction of 1.57 and an absorption coefficient of 0.005.

The weight median particle size is measured by the sedimentation method, which is an analysis method of sedimentation behavior in a gravity field. This measurement is made using the Sedigraph ^TM 5100 from the Micromeritics Instrument Corporation. This method and this device are known to those of skill in the art and are commonly used to determine the particle size of fillers and pigments. This measurement is performed in a 0.1 wt% Na ₄ P ₂ O ₇ aqueous solution. The sample is dispersed using a high speed stirrer and sonicated.

A vibrating sheave tower was used to analyze the particle size distribution of the granules. A fixed amount of 120 g of granules was placed on a steel wire screen (steel wire sieve; Retsch, Germany) with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm and 1 mm. The sheave tower was vibrated at 10 second intervals for 6 minutes with a vibration displacement of 1 mm.
This process and equipment is known to those of skill in the art and is commonly used to determine the particle size of fillers and pigments.

Surface reaction Intraparticle penetration ratio of calcium carbonate Pore volume (cm ³ / g)
The specific pore volume is mercury infusion using a Micromeritics Autopore V 9620 mercury porosimeter with a maximum applicable pressure of mercury of 414 MPa (60,000 psi), which is equivalent to a Laplace throttle diameter of 0.004 μm (~ nm). It is measured using the formula porosimeter measurement method. The equilibrium time used at each pressure step is 20 seconds. The sample material is sealed in a 5 cm ³ powder penetration meter chamber for analysis. The data are corrected for mercury compression, penetration meter expansion and sample material compression using the software Pore-Comp (Gane, PAC, Kettle, JP, Mathews, GP. ..

The total pore volume found in the integrated intrusion data can be divided into two regions with intrusion data ranging from 214 μm to about 1-4 μm, which indicates the coarse packing of the sample between any agglutinating structures that contribute strongly. Below these diameters, there is fine interparticle packing of the particles themselves. If the particle also has intraparticle pores, this region is bimodal and mercury is in the pores finer than the mode turning point, i.e. the pores finer than the bimodal inflection. The inflection specific pore volume is defined here as the intrusion specific pore volume. The sum of these three regions gives the overall pore volume of the sum of the powder, but is strongly dependent on the sedimentation of the powder in the original sample compression / coarse pore end distribution.

By taking the first derivative of the integrated penetration curve, the pore diameter distribution based on the equivalent of Laplace diameter, which inevitably includes pore shielding, becomes clear. These derivative curves clearly show the pore structure region of the coarse agglomerates, the interparticle pore region and, if present, the intraparticle pore region. Once the range of the intra-particle pore diameter is known, the remaining inter-particle pore volume and inter-aggregate pore volume are subtracted from the total pore volume and used as the pore volume per unit mass (as the specific pore volume) inside. The desired pore volume can be obtained for the pores only. Of course, the same deduction principle also applies when separating any other pore size region of interest.

Surface reaction Intraparticle penetration ratio of calcium carbonate Pore volume (cm ³ / g)
The specific pore volume is mercury infusion using a Micromeritics Autopore V 9620 mercury porosimeter with a maximum applicable pressure of mercury of 414 MPa (60,000 psi), which is equivalent to a Laplace throttle diameter of 0.004 μm (~ nm). It is measured using the formula porosimeter measurement method. The equilibrium time used at each pressure step is 20 seconds. The sample material is sealed in a 3 cm ³ powder penetration meter chamber for analysis. The data are corrected for mercury compression, penetration meter expansion and sample material compression using the software Pore-Comp (Gane, PAC, Kettle, JP, Mathews, GP. ..

The linear derivative of the integrated penetration curve, which indicates the intra-particle pore volume region and the inter-particle pore volume region, is not independent and is separable in all cases. Therefore, in order to show the difference in the pore volume of the sample carrying the active ingredient as compared with the granules without the active ingredient, the total penetration volume of the intra-particle pore volume and the inter-particle pore volume of the granular material is shown. The pore volume of each sample was determined by taking an integrated penetration curve for pore diameters less than 5 μm.

Granules of selected granule fractions (180 μm to 710 μm) with a bulk density of 120 g were sifted through a 0.5 mm screen using a brush. This sample of 100 ± 0.5 g was carefully filled into a 250 mL measuring cylinder using a powder funnel and its volume was read to the unit of 1 mL. The loose bulk density was calculated by the following formula:
Loose bulk density [g / mL] = bulk volume [mL] / sample weight [g]
Results were recorded to the unit of 0.01 g / mL.

Granules of selected granule fractions (180 μm to 710 μm) with a tap density of 120 g were sifted through a 0.5 mm screen using a brush. This sample of 100 ± 0.5 g was carefully filled into a 250 mL measuring cylinder using a powder funnel. Connect the graduated cylinder to a support with a drop device that can be tapped. The graduated cylinder is fixed to this support and reads the volume after 1250 taps. Subsequently, a second tapping step consisting of 1250 taps is performed, and the volume value is read. When the difference between the second tap volume value and the first tap volume value is 2 mL or less, the value of the second tap volume becomes the tap volume. When the difference between the second tap volume value and the first tap volume exceeds 2 mL, the tapping step is repeated 1250 times until the difference from the value in the next step becomes 2 mL or less.

Angle of repose Measure the angle of repose with a fluidity tester. A hopper with a 10 mm nozzle is filled with about 150 mL of granules. After emptying the hopper, the bevel angle of the granules is measured by a laser beam and the angle of repose is calculated. The angle of repose β is the angle of the inclined side surface with respect to the horizon and is calculated as shown below.

Compressibility index (compression degree)
The compressibility index is calculated as follows:
Compressibility index = (tap density-bulk density) / tap density ^* 100

TGA (thermogravimetric analysis)
TGA is basically used to measure the loss due to burning of mineral (inorganic) samples and filled organic substances. The device used to measure TGA was Mettler-Toledo TGA / DSC1 (TGA 1 STARE System) and the crucible used was made of 900 μL aluminum oxide. This method consists of two heating steps, the first step is a heating rate of 20 ° C./min for 10 minutes and 30-130 ° C., and the second step is a heating rate of 20 ° C./min for 20 minutes. , 130-570 ° C.

SEM (scanning electron microscope)
Samples for study by SEM were prepared by filtering the suspension and drying the resulting product at 110 ° C. in a drying oven. The sample was sputtered with 20 nm gold before taking SEM photographs.

2. 2. Material Surface Reactive Calcium Carbonate (FCC) (Omuya International AG, Switzerland) was considered equivalent to microcrystalline cellulose (Avicel® PH102, FMC Biopolymer, Ireland). The details of surface reaction calcium carbonate are summarized in Table 1 below:

As active ingredients, eugenol (≧ 98%, FCC, FG, sigma-aldrich, W246700, CAS No. 97-53-0, EC No. 202-589-1) and ibuprofen (Shashun Pharmaceutical Limited, BP / Ph. Eur. , CAS No. 15687-27-1) was selected.

3. 3. Granulation experiment
a) Granulation of FCC (surface reaction calcium carbonate) supporting eugenol by roller compression 300 g of FCC (d ₅₀ 6.13 μm, SSA 55.5 m ² / g) supported on FCC was placed in a 3 L plastic beaker. rice field. The powder was loaded with 33.4 g (10 wt%) or 100 g (25 wt%) of eugenol. Eugenol was supported by dropping at a rate of 1-2 drops / sec using a peristaltic pump Ismatec IPC8 with a 1.52 mm wide 2-stop tube. During the loading, the powder was constantly mixed by the overhead stirrer IKA RW20 at speeds ranging from 80 to 120 rpm using an open blade paddle mixer. After loading the entire amount of liquid on the FCC, the supported powder (post-supported powder) was continued to be mixed for an additional 10 minutes.

Granulation of FCC carrying eugenol was performed using Fitzpatchic CCS220. A bar mill and a 1 mm stone screen were used for granulation. The parameters set were as follows:
Roll gap 0.7 mm (actual value during processing: 0.9 rpm)
Roll force 5kN / cm
Roll speed 5 rpm
Horizontal screw speed 25 rpm (actual value at the time of processing: 13 rpm)
Vertical screw speed 250 rpm
Mill speed 300 rpm
Granule fractions of 250-710 μm were produced using a Retsch Tower Sheave Shaker (Vibration Sheave Tower) AS300 with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm and 1000 μm.

Results of Granules Obtained from FCCs Carrying Eugenol Granules could be produced from FCCs carrying 10% by weight and 25% by weight Eugenol.

The particle size distribution and additional parameters are listed in Tables 2, 3 and 4.

Scanning electron microscope (SEM) photographs of granules made from FCC carrying 10% by weight or 25% by weight of eugenol are shown in FIGS. 1 and 2.

Tablet molding of granules obtained from FCC carrying eugenol Granules obtained from FCC carrying eugenol were placed in a Turbula mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes in a 0.5 wt% lubricant (Turbula T10B). It was further mixed with magnesium stearate, Weighted MF-2-V, CAS No. 557-04-0, Peter Green). This mixture was further used to make tablets on the Fette 1200i with EU1'machinery equipment, with a 10 mm filling cam, eight standard convex 10 mm round punches, and a tableting speed of 15,000 tablets / hour. The depth was adjusted so that the compressive force was 2 kN, 4 kN and 6 kN, and the weight of the tablet was fixed at 175 mg. The parameters of the molded tablet are shown in Table 5.

b) Granulation of FCC (surface reaction calcium carbonate) supporting ibuprofen by roller compression 300 g of FCC (d ₅₀ 6.13 μm, SSA 55.5 m ² / g) supported on FCC was placed in a 3 L plastic beaker. rice field. This powder was loaded with 33.4 g (10 wt%) and 200 g (40 wt%) of ibuprofen (BASF). Ibuprofen was first dissolved in 150 g of acetone on a 10 wt% carrier and in 300 g of acetone on a 40 wt% carrier. An acetone solution of ibuprofen was carried by spraying with a spray bottle at a rate of 5 times every 15 seconds. During the loading, the powder was constantly mixed by the overhead stirrer IKA RW20 at speeds ranging from 80 to 120 rpm using an open blade paddle mixer. After loading the entire amount of the solution on the FCC, the supported powder was continued to be mixed for an additional 10 minutes. The supported powder (post-supported powder) was dried in a vacuum oven Thermo Scientific VT 6130 until the solvent was no longer recovered.

Granulation of FCC carrying ibuprofen was performed using Fitzpatchic CCS220. A bar mill and a 1 mm stone screen were used for granulation. The parameters set were as follows:

10 wt% ibuprofen roll gap 0.7 mm (actual value during processing: 0.8 rpm)
Roll force 3kN / cm
Roll speed 7 rpm
Horizontal screw speed 25 rpm (actual value at the time of processing: 13 rpm)
Vertical screw speed 250 rpm
Mill speed 300 rpm
Granule fractions of 250-710 μm were produced using a Retsch Tower Sheave Shaker (Vibration Sheave Tower) AS300 with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm and 1000 μm.

40% by weight ibuprofen roll gap 0.7 mm (actual value during processing: 0.8 rpm)
Roll force 3kN / cm
Roll speed 7 rpm
Horizontal screw speed 35 rpm (actual value at the time of processing: 25 rpm)
Vertical screw speed 250 rpm
Mill speed 300 rpm
Granule fractions of 250-710 μm were produced using a Retsch Tower Sheave Shaker (Vibration Sheave Tower) AS300 with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm and 1000 μm.

Results of Granules Obtained from FCCs Carrying Ibuprofen Granules could be produced from FCCs carrying 10% by weight and 40% by weight ibuprofen. The particle size distribution and additional parameters are listed in Tables 6, 7 and 8.

Scanning electron microscope (SEM) photographs of the FCC carrying 10% by weight or 40% by weight of ibuprofen are shown in FIGS. 3 and 4.

Tablet molding of granules obtained from FCC carrying ibuprofen Granules obtained from FCC carrying ibuprofen were placed in a Turbula mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes with 0.5% by weight of lubricant (Turbula T10B). Further mixed with magnesium stearate, Weighted MF-2-V, CAS No. 557-04-0, Peter Green). This mixture was further used to make tablets on the Fette 1200i with EU1'machinery equipment, with a 10 mm filling cam, eight standard convex 10 mm round punches, and a tableting speed of 15,000 tablets / hour. The depth was adjusted so that the compressive force was 2 kN, 4 kN and 6 kN, and the weight of the tablet was fixed at 175 mg. The parameters of the molded tablet are shown in Table 9.

The invention disclosed herein includes:
[1] A method for producing an administered preparation, which comprises the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a natural ground calcium carbonate or precipitated calcium carbonate in an aqueous medium, carbon dioxide and one or more Hs. ₃ O ^＋ It is a reaction product with an ion donor, and the carbon dioxide is the H. ₃ O ^＋ Formed in-situ by treatment with an ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reactive calcium carbonate obtained in step (c) is compressed by a roller compressor at a consolidation pressure in the range of 1 to 30 kN / cm to form a compressed form;
(E) The compressed form of step (d) is crushed into granules;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor.
[2] Is the natural ground calcium carbonate selected from calcium carbonates containing minerals selected from the group comprising marbles, whites, dolomites, limestones, and mixtures thereof; or the precipitated calcium carbonates of aragonite. The method according to [1], which is selected from the group containing precipitated calcium carbonate having a mineral crystal form of batelite or limestone, and a mixture thereof.
[3] The surface reaction calcium carbonate is
(A) Measured by the BET method according to ISO9277 using nitrogen, 20 m. ² / G-450m ² / G, preferably 20 m ² / G-250m ² / G, more preferably 30 m ² / G-160m ² / G, most preferably 40m ² / G-150m ² / G, more preferably 40m ² / G-140m ² Has a BET specific surface area of / g; and / or
(B) Volume median particle size d of 1 μm to 50 μm, preferably 1 μm to 45 μm, more preferably 2 μm to 30 μm, even more preferably 3 μm to 15 μm, most preferably 4 μm to 12 μm. ₅₀ Includes particles with; and / or
(C) 0.15 cm calculated from the measurement results with a mercury intrusion porosimeter. ³ / G ~ 1.35cm ³ / G, preferably 0.30 cm ³ / G ~ 1.30cm ³ / G, most preferably 0.40 cm ³ / G-1.25cm ³ It has an intraparticle penetration ratio pore volume in the range of / g;
The method according to [1] or [2].
[4] The at least one active ingredient and / or its inert precursor is a fragrance, a flavoring agent, an herb extract, a fruit extract, a nutrient, a trace mineral, a repellent, a food, a cosmetic, a flame retardant, an enzyme, and the like. Polymers, pesticides, fertilizers, preservatives, antioxidants, reactive chemicals, synthetically-originating, semi-synthetic or naturally-occurring pharmaceutically active agents or their pharmaceutically inactive precursors, and mixtures thereof. The method according to any one of [1] to [3], which is selected from the including group.
[5] The at least one active ingredient and / or its inert precursor is in the form of a liquid, preferably the at least one active ingredient and / or its inert precursor is provided in a solvent, preferably. The solvents used are water, methanol, ethanol, n-butanol, isopropanol, n-propanol, n-octanol, acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, vegetable oils and derivatives thereof, animal oils and derivatives thereof, molten fats and waxes. The method according to any one of [1] to [4], wherein the solvent is selected from the group containing a mixture thereof, and more preferably the solvent is water, ethanol and / or acetone.
[6] In the carrying step (c), the at least one active ingredient and / or its inert precursor is sprayed or dropped onto the surface-reacted calcium carbonate, and a fluidized bed dryer / granulator / plow shear. The invention according to any one of [1] to [5], which is carried out by mixing in an apparatus selected from the group including a mixer, a vertical or horizontal mixer, a high shear or low shear mixer, and a high speed blender. the method of.
[7] The compression step (d) by the roller compressor is performed at a roller consolidation pressure in the range of 1 to 28 kN /, more preferably in the range of 1 to 20 kN / cm, and most preferably in the range of 2 to 10 kN / cm. The method according to any one of [1] to [6].
[8] The method according to any one of [1] to [7], further comprising a step (f) of sieving the granules of the step (e) by at least one mesh size.
[9] Step (b1) for providing at least one compounding aid and
The granules obtained in step (e) and / or the granules obtained in step (f) when performed are mixed with the at least one compounding aid of step (b1) and / or step (b1). Mixing and / or coating step (c1) of coating with at least one compounding aid of the above.
The method according to any one of [1] to [8], further comprising.
[10] The at least one compounding aid is a disintegrant, preferably a modified cellulose gum, an insoluble crosslinked polyvinylpyrrolidone, a starch glycolate, a microcrystalline cellulose, an pregelatinized starch, a sodium carboxymethyl starch, a low-substituted hydroxypropyl cellulose, and the like. Homopolymer of N-vinyl-2-pyrrolidone, alkyl cellulose ester, hydroxyalkyl cellulose ester, carboxyalkyl cellulose ester, alginate, microcrystalline cellulose and its crystalline polymorph, ion exchange resin, gum, chitin, chitosan, clay, gellan gum, Disintegrants selected from the group containing crosslinked polar crilin copolymers, agar, gelatin, dextrin, acrylic acid polymers, sodium carboxymethyl cellulose / calcium, hydroxypropylmethyl cellulose phthalates, shelac, or mixtures thereof; lubricants, especially internal lubricants. And / or external lubricants; impact modifiers; plasticizers; waxes; stabilizers; pigments; colorants; flavoring agents; flavoring agents; flavoring agents; sweeteners; texture improving agents; diluents; film forming agents; The method according to [9], which is selected from the group containing an adhesive; a buffer; an adsorbent; an odor masking agent; and a mixture thereof.
[11] The sieving step (f) is performed by sieving more than two or more different mesh sizes, preferably 180 μm, 250 μm, 355 μm, 500 μm and 710 μm mesh sizes. , [8] to [10].
[12] The granules obtained in the step (e) or, if performed, the granules obtained in the step (f) and / or the step (c1) are tablet-molded, or the granules obtained in the step (e) or The method according to any one of [1] to [11], further comprising a step (g) of filling the capsule with the granules obtained in the step (f) and / or the step (c1).
[13] Granules obtained by the method according to any one of [1] to [11].
[14] Tablets and / or capsules obtained by the method according to [12].
[15] A pharmaceutical product, preferably a tablet, a mini-tablet or a capsule, comprising the granules according to [13].
[16] The granules according to [13], or the tablets and / or capsules according to [14], or [16] in pharmaceutical products, dietary supplements, pesticides, cosmetics, household products, foods, packages and personal care products. 15] Use of the administered preparation according to.
[17] Pharmaceuticals, dietary supplements, pesticides, cosmetics, household products, including the granules according to [13], or the tablets and / or capsules according to [14], or the pharmaceutical product according to [15]. Food, packaging and personal care products.
[18] Use of surface-reactive calcium carbonate in the method according to any one of [1] to [12].

Claims (16)

Method for producing a pharmaceutical product, which comprises the following steps:
(A) To provide surface reaction calcium carbonate,
Here, the surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more _H3O ⁺ ion donors in an aqueous medium, and the dioxide. Carbon is in-situ formed by treatment with the _H3O ⁺ ion donor and / or supplied from an external source;
(B) To provide at least one active ingredient and / or its inert precursor;
(C) The at least one active ingredient of step (b) and / or its inert precursor thereof is carried on the surface-reacted calcium carbonate of step (a);
(D) The supported surface-reacted calcium carbonate obtained in step (c) is compressed by a roller compressor with a roller compaction pressure as a linear pressure in the range of 2 to 10 kN / cm to form a compressed form. matter;
(E) The compressed form of step (d) is crushed into granules; and (f) the granules of step (e) are two or more different within the range of 180-710 μm. Sift mesh size ;
However, the compressed form of the carried surface-reactive calcium carbonate obtained in step (d) is the surface-reactive calcium carbonate of step (a) and the at least one active ingredient of step (b) and /. Or it consists of its inert precursor. Is the natural ground calcium carbonate selected from calcium carbonates containing minerals selected from the group containing marbles, whites, dolomites, limestones, and mixtures thereof; or the precipitated calcium carbonates are aragonite, vaterite or The method according to claim 1, which is selected from the group containing precipitated calcium carbonate having a mineral crystalline form of calcite and a mixture thereof. The surface reaction calcium carbonate is
(A) has a BET specific surface area of 20 m ² / g to 450 m ² / g as measured by the ISO 9277 BET method using nitrogen; and / or (b) has a volume median particle size d ₅₀ of 1 μm to 50 μm. Contains particles; and / or (c) has an in-particle penetration specific surface area in the range of 0.15 cm ³ / g to 1.35 cm ³ / g, calculated from measurements on a mercury intrusion porosimeter;
The method according to claim 1 or 2. The at least one active ingredient and / or its inert precursor is a fragrance, a flavoring agent, an herb extract, a fruit extract, a nutrient, a trace mineral, a repellent, a food, a cosmetic, a flame retardant, an enzyme, a polymer, and the like. From groups containing pesticides, fertilizers, preservatives, antioxidants, reactive chemicals, synthetically-originating, semi-synthetic or naturally-occurring pharmaceutically active agents or their pharmaceutically inactive precursors, and mixtures thereof. The method according to any one of claims 1 to 3, which is selected. The method according to any one of claims 1 to 4, wherein the at least one active ingredient and / or its inert precursor is in the form of a liquid. The method according to any one of claims 1 to 5, wherein the at least one active ingredient and / or its inert precursor is provided in a solvent. The solvents include water, methanol, ethanol, n-butanol, isopropanol, n-propanol, n-octanol, acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, vegetable oils and derivatives thereof, animal oils and derivatives thereof, molten fats and waxes, and The method of claim 6, selected from the group comprising these mixtures. In the carrying step (c), the at least one active ingredient and / or its inert precursor is sprayed or dropped onto the surface-reactive calcium carbonate, and a fluidized bed dryer / granulator, a plow shear mixer, a vertical. The method according to any one of claims 1 to 7, wherein the method is carried out by mixing in an apparatus selected from the group including a horizontal mixer, a high shear or low shear mixer, and a high speed blender. The method according to any one of claims 1 to 8, wherein the compression step (d) by a roller compressor is performed at a roller consolidation pressure as a linear pressure of 5 kN / cm. The granules obtained in the step (b1) and the step (e) and / or the granules obtained in the step (f) for providing at least one compounding aid are combined with the at least one compounding aid in the step (b1). Mixing and / or coating step (c1) of mixing and / or coating with at least one of the compounding aids of step (b1).
The method according to any one of claims 1 to 9, further comprising. The at least one compounding aid is a disintegrant; a lubricant, particularly an internal lubricant and / or an external lubricant; an impact modifier; a plasticizer; a wax; a stabilizer; a pigment; a colorant; a flavoring agent; a flavoring agent. The tenth aspect of claim 10, wherein the agent is selected from the group containing an agent; a flavoring agent; a sweetening agent; a texture improving agent; a diluent; a film forming agent; an adhesive; a buffering agent; an adsorbent; an odor masking agent; and a mixture thereof. the method of. The disintegrant is modified cellulose gum, insoluble crosslinked polyvinylpyrrolidone, starch glycolate, microcrystalline cellulose, pregelatinized cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, homopolymer of N-vinyl-2-pyrrolidone, alkyl cellulose. Esters, hydroxyalkyl cellulose esters, carboxyalkyl cellulose esters, alginates, microcrystalline cellulose and its crystalline polymorphs, ion exchange resins, gums, chitins, chitosans, clays, gellan gums, crosslinked polarcryline copolymers, agar, gelatin, dextrin, acrylic acids. 11. The method of claim 11, selected from the group comprising a polymer, sodium carboxymethyl cellulose / calcium, hydroxypropylmethyl cellulose phthalate, shelac, or a mixture thereof. The sieving step (f) is performed by sieving two or more different mesh sizes selected from the group consisting of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm mesh sizes. Item 9. The method according to any one of Items 9 to 12. The granules obtained in step (e) or the granules obtained in step (f) and / or the granules obtained in step (c1) are tablet-molded, or the granules obtained in step (e) or steps (f) and / or The method according to any one of claims 1 to 13, further comprising a step (g) of filling the capsule with the granules obtained in the step (c1). The method according to any one of claims 1 to 14, for producing pharmaceuticals, dietary supplements, pesticides, cosmetics, household products, foods, packages and personal care products. Use of the surface-reactive calcium carbonate for the method according to any one of claims 1-15.

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